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Sample records for cell regeneration research

  1. [Research progress of intervertebral disc endogenous stem cells for intervertebral disc regeneration].

    Liang, Hang; Deng, Xiangyu; Shao, Zengwu

    2017-10-01

    To summarize the research progress of intervertebral disc endogenous stem cells for intervertebral disc regeneration and deduce the therapeutic potential of endogenous repair for intervertebral disc degeneration. The original articles about intervertebral disc endogenous stem cells for intervertebral disc regeneration were extensively reviewed; the reparative potential in vivo and the extraction and identification in vitro of intervertebral disc endogenous stem cells were analyzed; the prospect of endogenous stem cells for intervertebral disc regeneration was predicted. Stem cell niche present in the intervertebral discs, from which stem cells migrate to injured tissues and contribute to tissues regeneration under certain specific microenvironment. Moreover, the migration of stem cells is regulated by chemokines system. Tissue specific progenitor cells have been identified and successfully extracted and isolated. The findings provide the basis for biological therapy of intervertebral disc endogenous stem cells. Intervertebral disc endogenous stem cells play a crucial role in intervertebral disc regeneration. Therapeutic strategy of intervertebral disc endogenous stem cells is proven to be a promising biological approach for intervertebral disc regeneration.

  2. Cell migration during heart regeneration in zebrafish.

    Tahara, Naoyuki; Brush, Michael; Kawakami, Yasuhiko

    2016-07-01

    Zebrafish possess the remarkable ability to regenerate injured hearts as adults, which contrasts the very limited ability in mammals. Although very limited, mammalian hearts do in fact have measurable levels of cardiomyocyte regeneration. Therefore, elucidating mechanisms of zebrafish heart regeneration would provide information of naturally occurring regeneration to potentially apply to mammalian studies, in addition to addressing this biologically interesting phenomenon in itself. Studies over the past 13 years have identified processes and mechanisms of heart regeneration in zebrafish. After heart injury, pre-existing cardiomyocytes dedifferentiate, enter the cell cycle, and repair the injured myocardium. This process requires interaction with epicardial cells, endocardial cells, and vascular endothelial cells. Epicardial cells envelope the heart, while endocardial cells make up the inner lining of the heart. They provide paracrine signals to cardiomyocytes to regenerate the injured myocardium, which is vascularized during heart regeneration. In addition, accumulating results suggest that local migration of these major cardiac cell types have roles in heart regeneration. In this review, we summarize the characteristics of various heart injury methods used in the research community and regeneration of the major cardiac cell types. Then, we discuss local migration of these cardiac cell types and immune cells during heart regeneration. Developmental Dynamics 245:774-787, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  3. Bone regeneration and stem cells

    Arvidson, K; Abdallah, B M; Applegate, L A; Baldini, N; Cenni, E; Gomez-Barrena, E; Granchi, D; Kassem, M; Konttinen, Y T; Mustafa, K; Pioletti, D P; Sillat, T; Finne-Wistrand, A

    2011-01-01

    Abstract This invited review covers research areas of central importance for orthopaedic and maxillofacial bone tissue repair, including normal fracture healing and healing problems, biomaterial scaffolds for tissue engineering, mesenchymal and foetal stem cells, effects of sex steroids on mesenchymal stem cells, use of platelet-rich plasma for tissue repair, osteogenesis and its molecular markers. A variety of cells in addition to stem cells, as well as advances in materials science to meet specific requirements for bone and soft tissue regeneration by addition of bioactive molecules, are discussed. PMID:21129153

  4. Bone regeneration and stem cells

    Arvidson, K; Abdallah, B M; Applegate, L A

    2011-01-01

    cells, use of platelet rich plasma for tissue repair, osteogenesis and its molecular markers. A variety of cells in addition to stem cells, as well as advances in materials science to meet specific requirements for bone and soft tissue regeneration by addition of bioactive molecules, are discussed.......This invited review covers research areas of central importance for orthopedic and maxillofacial bone tissue repair, including normal fracture healing and healing problems, biomaterial scaffolds for tissue engineering, mesenchymal and fetal stem cells, effects of sex steroids on mesenchymal stem...

  5. Mammalian Cochlear Hair Cell Regeneration and Ribbon Synapse Reformation

    Xiaoling Lu

    2016-01-01

    Full Text Available Hair cells (HCs are the sensory preceptor cells in the inner ear, which play an important role in hearing and balance. The HCs of organ of Corti are susceptible to noise, ototoxic drugs, and infections, thus resulting in permanent hearing loss. Recent approaches of HCs regeneration provide new directions for finding the treatment of sensor neural deafness. To have normal hearing function, the regenerated HCs must be reinnervated by nerve fibers and reform ribbon synapse with the dendrite of spiral ganglion neuron through nerve regeneration. In this review, we discuss the research progress in HC regeneration, the synaptic plasticity, and the reinnervation of new regenerated HCs in mammalian inner ear.

  6. Potential Use of Stem Cells for Kidney Regeneration

    Takashi Yokoo

    2011-01-01

    Full Text Available Significant advances have been made in stem cell research over the past decade. A number of nonhematopoietic sources of stem cells (or progenitor cells have been identified, including endothelial stem cells and neural stem cells. These discoveries have been a major step toward the use of stem cells for potential clinical applications of organ regeneration. Accordingly, kidney regeneration is currently gaining considerable attention to replace kidney dialysis as the ultimate therapeutic strategy for renal failure. However, due to anatomic complications, the kidney is believed to be the hardest organ to regenerate; it is virtually impossible to imagine such a complicated organ being completely rebuilt from pluripotent stem cells by gene or chemical manipulation. Nevertheless, several groups are taking on this big challenge. In this manuscript, current advances in renal stem cell research are reviewed and their usefulness for kidney regeneration discussed. We also reviewed the current knowledge of the emerging field of renal stem cell biology.

  7. Fuel cell catholyte regenerating apparatus

    Struthers, R. C.

    1985-01-01

    A catholyte regenerating apparatus for a fuel cell having a cathode section containing a catholyte solution and wherein fuel cell reaction reduces the catholyte to gas and water. The apparatus includes means to conduct partically reduced water diluted catholyte from the fuel cell and means to conduct the gas from the fuel cell to a mixing means. An absorption tower containing a volume of gas absorbing liquid solvent receives the mixed together gas and diluted catholyte from the mixing means within the absorption column, the gas is absorbed by the solvent and the gas ladened solvent and diluted catholyte are commingled. A liquid transfer means conducts gas ladened commingled. A liquid transfer means conducts gas ladened commingled solvent and electrolyte from the absorption column to an air supply means wherein air is added and commingled therewith and a stoichiometric volume of oxygen from the air is absorbed thereby. A second liquid transfer means conducts the gas ladened commingled solvent and diluted catholyte into a catalyst column wherein the oxygen and gas react to reconstitute the catholyte from which the gas was generated wna wherein the reconstituted diluted catholyte is separated from the solvent. Recirculating means conducts the solvent from the catalyst column back into the absorption column and liquid conducting means conducts the reconstituted catholyte to a holding tank preparatory for catholyte to a holding tank preparatory for recirculation through the cathode section of the fuel cell

  8. Sensory hair cell death and regeneration in fishes

    Jerry D. Monroe

    2015-04-01

    Full Text Available Sensory hair cells are specialized mechanotransductive receptors required for hearing and vestibular function. Loss of hair cells in humans and other mammals is permanent and causes reduced hearing and balance. In the early 1980’s, it was shown that hair cells continue to be added to the inner ear sensory epithelia in cartilaginous and bony fishes. Soon thereafter, hair cell regeneration was documented in the chick cochlea following acoustic trauma. Since then, research using chick and other avian models has led to great insights into hair cell death and regeneration. However, with the rise of the zebrafish as a model organism for studying disease and developmental processes, there has been an increased interest in studying sensory hair cell death and regeneration in its lateral line and inner ears. Advances derived from studies in zebrafish and other fish species include understanding the effect of ototoxins on hair cells and finding otoprotectants to mitigate ototoxin damage, the role of cellular proliferation versus direct transdifferentiation during hair cell regeneration, and elucidating cellular pathways involved in the regeneration process. This review will summarize research on hair cell death and regeneration using fish models, indicate the potential strengths and weaknesses of these models, and discuss several emerging areas of future studies.

  9. The TMI regenerable solid oxide fuel cell

    Cable, Thomas L.

    1995-04-01

    Energy storage and production in space requires rugged, reliable hardware which minimizes weight, volume, and maintenance while maximizing power output and usable energy storage. These systems generally consist of photovoltaic solar arrays which operate during sunlight cycles to provide system power and regenerate fuel (hydrogen) via water electrolysis; during dark cycles, hydrogen is converted by the fuel cell into system. The currently preferred configuration uses two separate systems (fuel cell and electrolyzer) in conjunction with photovoltaic cells. Fuel cell/electrolyzer system simplicity, reliability, and power-to-weight and power-to-volume ratios could be greatly improved if both power production (fuel cell) and power storage (electrolysis) functions can be integrated into a single unit. The Technology Management, Inc. (TMI), solid oxide fuel cell-based system offers the opportunity to both integrate fuel cell and electrolyzer functions into one unit and potentially simplify system requirements. Based an the TMI solid oxide fuel cell (SOPC) technology, the TMI integrated fuel cell/electrolyzer utilizes innovative gas storage and operational concepts and operates like a rechargeable 'hydrogen-oxygen battery'. Preliminary research has been completed on improved H2/H2O electrode (SOFC anode/electrolyzer cathode) materials for solid oxide, regenerative fuel cells. Improved H2/H2O electrode materials showed improved cell performance in both fuel cell and electrolysis modes in reversible cell tests. ln reversible fuel cell/electrolyzer mode, regenerative fuel cell efficiencies (ratio of power out (fuel cell mode) to power in (electrolyzer model)) improved from 50 percent (using conventional electrode materials) to over 80 percent. The new materials will allow the TMI SOFC system to operate as both the electrolyzer and fuel cell in a single unit. Preliminary system designs have also been developed which indicate the technical feasibility of using the TMI SOFC

  10. Challenges of stem cell-based pulp and dentin regeneration: a clinical perspective.

    Huang, George T-J; Al-Habib, Mey; Gauthier, Philippe

    2013-03-01

    There are two types of approaches to regenerate tissues: cell-based and cell-free. The former approach is to introduce exogenous cells into the host to regenerate tissues, and the latter is to use materials other than cells in an attempt to regenerate tissues. There has been a significant advancement in stem cell-based pulp and dentin regeneration research in the past few years. Studies in small and large animals have demonstrated that pulp/dentin-like tissues can be regenerated partially or completely in the root canal space with apical openings of 0.7-3.0 mm using dental pulp stem cells, including stem cells from apical papilla (SCAP) and subpopulations of pulp stem cells. Bone marrow mesenchymal stem cells (BMMSCs) and adipose tissue-derived MSCs (ADMSCs) have also been shown to regenerate pulp-like tissue. In contrast, the cell-free approach has not produced convincing evidence on pulp regeneration. However, one crucial concept has not been considered nor defined in the field of pulp/dentin regeneration and that is the critical size defect of dentin and pulp. Without such consideration and definition, it is difficult to predict or anticipate the extent of cell-free pulp regeneration that would occur. By reasoning, cell-free therapy is unlikely to regenerate an organ/tissue after total loss. Similarly, after a total loss of pulp, it is unlikely to regenerate without using exogenously introduced cells. A cell homing approach may provide a limited amount of tissue regeneration. Although stem cell-based pulp/dentin regeneration has shown great promise, clinical trials are difficult to launch at present. This article will address several issues that challenge and hinder the clinical applications of pulp/dentin regeneration which need to be overcome before stem cell-based pulp/dentin regeneration can occur in the clinic.

  11. Endothelial-regenerating cells: an expanding universe.

    Steinmetz, Martin; Nickenig, Georg; Werner, Nikos

    2010-03-01

    Atherosclerosis is the most common cause for cardiovascular diseases and is based on endothelial dysfunction. A growing body of evidence suggests the contribution of bone marrow-derived endothelial progenitor cells, monocytic cells, and mature endothelial cells to vessel formation and endothelial rejuvenation. To this day, various subsets of these endothelial-regenerating cells have been identified according to cellular origin, phenotype, and properties in vivo and in vitro. However, the definition and biology, especially of endothelial progenitor cells, is complex and under heavy debate. In this review, we focus on current definitions of endothelial progenitor cells, highlight the clinical relevance of endothelial-regenerating cells, and provide new insights into cell-cell interactions involved in endothelial cell rejuvenation.

  12. Sensory hair cell regeneration in the zebrafish lateral line.

    Lush, Mark E; Piotrowski, Tatjana

    2014-10-01

    Damage or destruction of sensory hair cells in the inner ear leads to hearing or balance deficits that can be debilitating, especially in older adults. Unfortunately, the damage is permanent, as regeneration of the inner ear sensory epithelia does not occur in mammals. Zebrafish and other non-mammalian vertebrates have the remarkable ability to regenerate sensory hair cells and understanding the molecular and cellular basis for this regenerative ability will hopefully aid us in designing therapies to induce regeneration in mammals. Zebrafish not only possess hair cells in the ear but also in the sensory lateral line system. Hair cells in both organs are functionally analogous to hair cells in the inner ear of mammals. The lateral line is a mechanosensory system found in most aquatic vertebrates that detects water motion and aids in predator avoidance, prey capture, schooling, and mating. Although hair cell regeneration occurs in both the ear and lateral line, most research to date has focused on the lateral line due to its relatively simple structure and accessibility. Here we review the recent discoveries made during the characterization of hair cell regeneration in zebrafish. Copyright © 2014 Wiley Periodicals, Inc.

  13. SENSORY HAIR CELL REGENERATION IN THE ZEBRAFISH LATERAL LINE

    Lush, Mark E.; Piotrowski, Tatjana

    2014-01-01

    Damage or destruction of sensory hair cells in the inner ear leads to hearing or balance deficits that can be debilitating, especially in older adults. Unfortunately, the damage is permanent, as regeneration of the inner ear sensory epithelia does not occur in mammals. Zebrafish and other non-mammalian vertebrates have the remarkable ability to regenerate sensory hair cells and understanding the molecular and cellular basis for this regenerative ability will hopefully aid us in designing therapies to induce regeneration in mammals. Zebrafish not only possess hair cells in the ear but also in the sensory lateral line system. Hair cells in both organs are functionally analogous to hair cells in the inner ear of mammals. The lateral line is a mechanosensory system found in most aquatic vertebrates that detects water motion and aids in predator avoidance, prey capture, schooling and mating. Although hair cell regeneration occurs in both the ear and lateral line, most research to date has focused on the lateral line due to its relatively simple structure and accessibility. Here we review the recent discoveries made during the characterization of hair cell regeneration in zebrafish. PMID:25045019

  14. Myocardial regeneration potential of adipose tissue-derived stem cells

    Bai, Xiaowen, E-mail: baixw01@yahoo.com [Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030 (United States); Alt, Eckhard, E-mail: ealt@mdanderson.org [Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030 (United States)

    2010-10-22

    Research highlights: {yields} Various tissue resident stem cells are receiving tremendous attention from basic scientists and clinicians and hold great promise for myocardial regeneration. {yields} For practical reasons, human adipose tissue-derived stem cells are attractive stem cells for future clinical application in repairing damaged myocardium. {yields} This review summarizes the characteristics of cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential and the, underlying mechanisms, and safety issues. -- Abstract: Various tissue resident stem cells are receiving attention from basic scientists and clinicians as they hold promise for myocardial regeneration. For practical reasons, adipose tissue-derived stem cells (ASCs) are attractive cells for clinical application in repairing damaged myocardium based on the following advantages: abundant adipose tissue in most patients and easy accessibility with minimally invasive lipoaspiration procedure. Several recent studies have demonstrated that both cultured and freshly isolated ASCs could improve cardiac function in animal model of myocardial infarction. The mechanisms underlying the beneficial effect of ASCs on myocardial regeneration are not fully understood. Growing evidence indicates that transplantation of ASCs improve cardiac function via the differentiation into cardiomyocytes and vascular cells, and through paracrine pathways. Paracrine factors secreted by injected ASCs enhance angiogenesis, reduce cell apoptosis rates, and promote neuron sprouts in damaged myocardium. In addition, Injection of ASCs increases electrical stability of the injured heart. Furthermore, there are no reported cases of arrhythmia or tumorigenesis in any studies regarding myocardial regeneration with ASCs. This review summarizes the characteristics of both cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential, and the

  15. Myocardial regeneration potential of adipose tissue-derived stem cells

    Bai, Xiaowen; Alt, Eckhard

    2010-01-01

    Research highlights: → Various tissue resident stem cells are receiving tremendous attention from basic scientists and clinicians and hold great promise for myocardial regeneration. → For practical reasons, human adipose tissue-derived stem cells are attractive stem cells for future clinical application in repairing damaged myocardium. → This review summarizes the characteristics of cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential and the, underlying mechanisms, and safety issues. -- Abstract: Various tissue resident stem cells are receiving attention from basic scientists and clinicians as they hold promise for myocardial regeneration. For practical reasons, adipose tissue-derived stem cells (ASCs) are attractive cells for clinical application in repairing damaged myocardium based on the following advantages: abundant adipose tissue in most patients and easy accessibility with minimally invasive lipoaspiration procedure. Several recent studies have demonstrated that both cultured and freshly isolated ASCs could improve cardiac function in animal model of myocardial infarction. The mechanisms underlying the beneficial effect of ASCs on myocardial regeneration are not fully understood. Growing evidence indicates that transplantation of ASCs improve cardiac function via the differentiation into cardiomyocytes and vascular cells, and through paracrine pathways. Paracrine factors secreted by injected ASCs enhance angiogenesis, reduce cell apoptosis rates, and promote neuron sprouts in damaged myocardium. In addition, Injection of ASCs increases electrical stability of the injured heart. Furthermore, there are no reported cases of arrhythmia or tumorigenesis in any studies regarding myocardial regeneration with ASCs. This review summarizes the characteristics of both cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential, and the underlying

  16. Role of the immune system in regeneration and its dynamic interplay with adult stem cells.

    Abnave, Prasad; Ghigo, Eric

    2018-04-09

    The immune system plays an indispensable role in the process of tissue regeneration following damage as well as during homeostasis. Inflammation and immune cell recruitment are signs of early onset injury. At the wound site, immune cells not only help to clear debris but also secrete numerous signalling molecules that induce appropriate cell proliferation and differentiation programmes essential for successful regeneration. However, the immune system does not always perform a complementary role in regeneration and several reports have suggested that increased inflammation can inhibit the regeneration process. Successful regeneration requires a balanced immune cell response, with the recruitment of accurately polarised immune cells in an appropriate quantity. The regulatory interactions of the immune system with regeneration are not unidirectional. Stem cells, as key players in regeneration, can also modulate the immune system in several ways to facilitate regeneration. In this review, we will focus on recent research demonstrating the key role of immune system in the regeneration process as well as the immunomodulatory effects of stem cells. Finally, we propose that research investigating the interplay between the immune system and stem cells within highly regenerating animals can benefit the identification of the key interactions and molecules required for successful regeneration. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. Mesenchymal stem cells in cartilage regeneration.

    Savkovic, Vuk; Li, Hanluo; Seon, Jong-Keun; Hacker, Michael; Franz, Sandra; Simon, Jan-Christoph

    2014-01-01

    Articular cartilage provides life-long weight-bearing and mechanical lubrication with extraordinary biomechanical performance and simple structure. However, articular cartilage is apparently vulnerable to multifactorial damage and insufficient to self-repair, isolated in articular capsule without nerves or blood vessels. Osteoarthritis (OA) is known as a degenerative articular cartilage deficiency progressively affecting large proportion of the world population, and restoration of hyaline cartilage is clinical challenge to repair articular cartilage lesion and recreate normal functionality over long period. Mesenchymal stem cells (MSC) are highly proliferative and multipotent somatic cells that are able to differentiate mesoderm-derived cells including chondrocytes and osteoblasts. Continuous endeavors in basic research and preclinical trial have achieved promising outcomes in cartilage regeneration using MSCs. This review focuses on rationale and technologies of MSC-based hyaline cartilage repair involving tissue engineering, 3D biomaterials and growth factors. By comparing conventional treatment and current research progress, we describe insights of advantage and challenge in translation and application of MSC-based chondrogenesis for OA treatment.

  18. Hypertranscription in development, stem cells, and regeneration

    Percharde, Michelle; Bulut-Karslioglu, Aydan; Ramalho-Santos, Miguel

    2016-01-01

    SUMMARY Cells can globally up-regulate their transcriptome during specific transitions, a phenomenon called hypertranscription. Evidence for hypertranscription dates back over 70 years, but it has gone largely ignored in the genomics era until recently. We discuss data supporting the notion that hypertranscription is a unifying theme in embryonic development, stem cell biology, regeneration and cell competition. We review the history, methods for analysis, underlying mechanisms and biological significance of hypertranscription. PMID:27989554

  19. Stem cells to regenerate the newborn brain

    van Velthoven, C.T.J.

    2011-01-01

    Perinatal hypoxia-ischemia (HI) is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. In this thesis we investigate whether mesenchymal stem cells (MSC) regenerate the neonatal brain after HI injury. We show that transplantation of MSC after neonatal brain injury

  20. Stem Cells in Tissue Repair and Regeneration

    Falanga, Vincent

    2012-01-01

    The field of tissue repair and wound healing has blossomed in the last 30 years. We have gone from recombinant growth factors, to living tissue engineering constructs, to stem cells. The task now is to pursue true regeneration, thus achieving full restoration of structures and their function.

  1. Regeneration of hair cells in the mammalian vestibular system.

    Li, Wenyan; You, Dan; Chen, Yan; Chai, Renjie; Li, Huawei

    2016-06-01

    Hair cells regenerate throughout the lifetime of non-mammalian vertebrates, allowing these animals to recover from hearing and balance deficits. Such regeneration does not occur efficiently in humans and other mammals. Thus, balance deficits become permanent and is a common sensory disorder all over the world. Since Forge and Warchol discovered the limited spontaneous regeneration of vestibular hair cells after gentamicininduced damage in mature mammals, significant efforts have been exerted to trace the origin of the limited vestibular regeneration in mammals after hair cell loss. Moreover, recently many strategies have been developed to promote the hair cell regeneration and subsequent functional recovery of the vestibular system, including manipulating the Wnt, Notch and Atoh1. This article provides an overview of the recent advances in hair cell regeneration in mammalian vestibular epithelia. Furthermore, this review highlights the current limitations of hair cell regeneration and provides the possible solutions to regenerate functional hair cells and to partially restore vestibular function.

  2. Perspectives on stem cell therapy for cardiac regeneration. Advances and challenges.

    Choi, Sung Hyun; Jung, Seok Yun; Kwon, Sang-Mo; Baek, Sang Hong

    2012-01-01

    Ischemic heart disease (IHD) accelerates cardiomyocyte loss, but the developing stem cell research could be useful for regenerating a variety of tissue cells, including cardiomyocytes. Diverse sources of stem cells for IHD have been reported, including embryonic stem cells, induced pluripotent stem cells, skeletal myoblasts, bone marrow-derived stem cells, mesenchymal stem cells, and cardiac stem cells. However, stem cells have unique advantages and disadvantages for cardiac tissue regeneration, which are important considerations in determining the specific cells for improving cell survival and long-term engraftment after transplantation. Additionally, the dosage and administration method of stem cells need to be standardized to increase stability and efficacy for clinical applications. Accordingly, this review presents a summary of the stem cell therapies that have been studied for cardiac regeneration thus far, and discusses the direction of future cardiac regeneration research for stem cells.

  3. Cancer-related aspects of regeneration research: a review

    Donaldson, D.J.; Mason, J.M.

    1975-01-01

    Tissue regeneration is simply the replacement of lost cells of a tissue by those remaining. Epimorphic regeneration involves dedifferentiation of many tissues and their organization into a blastema which eventually differentiates into the missing part, usually an appendage. A detailed comparison of the cell membrane changes occurring in epimorphic regeneration, tissue regeneration and cancer can contribute to greater understanding of the differences between normal and tumor cells. Further, there is evidence that epimorphic regeneration fields may in some instances suppress tumor induction and control existing tumors. This influence may be mediated by bioelectric fields, which are ubiquitous in nature and appear to control many cellular events. Disruption of these bioelectric fields suppresses epimorphic regeneration and may lead to cancer in mammals, while applied electric fields alter regenerative events and cause tumor regression. Studies on x-radioinduced regeneration suppression in relation to mutagenesis are also reviewed

  4. Regulatory T cells and skeletal muscle regeneration.

    Schiaffino, Stefano; Pereira, Marcelo G; Ciciliot, Stefano; Rovere-Querini, Patrizia

    2017-02-01

    Skeletal muscle regeneration results from the activation and differentiation of myogenic stem cells, called satellite cells, located beneath the basal lamina of the muscle fibers. Inflammatory and immune cells have a crucial role in the regeneration process. Acute muscle injury causes an immediate transient wave of neutrophils followed by a more persistent infiltration of M1 (proinflammatory) and M2 (anti-inflammatory/proregenerative) macrophages. New studies show that injured muscle is also infiltrated by a specialized population of regulatory T (Treg) cells, which control both the inflammatory response, by promoting the M1-to-M2 switch, and the activation of satellite cells. Treg cells accumulate in injured muscle in response to specific cytokines, such as IL-33, and promote muscle growth by releasing growth factors, such as amphiregulin. Muscle repair during aging is impaired due to reduced number of Treg cells and can be enhanced by IL-33 supplementation. Migration of Treg cells could also contribute to explain the effect of heterochronic parabiosis, whereby muscle regeneration of aged mice can be improved by a parabiotically linked young partners. In mdx dystrophin-deficient mice, a model of human Duchenne muscular dystrophy, muscle injury, and inflammation is mitigated by expansion of the Treg-cell population but exacerbated by Treg-cell depletion. These findings support the notion that immunological mechanisms are not only essential in the response to pathogenic microbes and tumor cells but also have a wider homeostatic role in tissue repair, and open new perspectives for boosting muscle growth in chronic muscle disease and during aging. © 2016 Federation of European Biochemical Societies.

  5. Stem Cell Therapy in Wound Healing and Tissue Regeneration

    Anna Meiliana

    2016-08-01

    a novel approach to many diseases. SUMMARY: Wound healing therapies continue to rapidly evolve, with advances in basic science and engineering research heralding the development of new therapies, as well as ways to modify existing treatments. Stem cell-based therapy is one of the most promising therapeutic concepts for wound healing. Advances in stem cell biology have enabled researchers and clinicians alike with access to cells capable of actively modulating the healing response.  KEYWORDS: wound healing, tissue regeneration, stem cells therapy

  6. Endogenous retinal neural stem cell reprogramming for neuronal regeneration

    Romain Madelaine

    2017-01-01

    Full Text Available In humans, optic nerve injuries and associated neurodegenerative diseases are often followed by permanent vision loss. Consequently, an important challenge is to develop safe and effective methods to replace retinal neurons and thereby restore neuronal functions and vision. Identifying cellular and molecular mechanisms allowing to replace damaged neurons is a major goal for basic and translational research in regenerative medicine. Contrary to mammals, the zebrafish has the capacity to fully regenerate entire parts of the nervous system, including retina. This regenerative process depends on endogenous retinal neural stem cells, the Müller glial cells. Following injury, zebrafish Müller cells go back into cell cycle to proliferate and generate new neurons, while mammalian Müller cells undergo reactive gliosis. Recently, transcription factors and microRNAs have been identified to control the formation of new neurons derived from zebrafish and mammalian Müller cells, indicating that cellular reprogramming can be an efficient strategy to regenerate human retinal neurons. Here we discuss recent insights into the use of endogenous neural stem cell reprogramming for neuronal regeneration, differences between zebrafish and mammalian Müller cells, and the need to pursue the identification and characterization of new molecular factors with an instructive and potent function in order to develop theurapeutic strategies for eye diseases.

  7. Biotechnology in the Treatment of Sensorineural Hearing Loss: Foundations and Future of Hair Cell Regeneration

    Parker, Mark A.

    2011-01-01

    Purpose: To provide an overview of the methodologies involved in the field of hair cell regeneration. First, the author provides a tutorial on the biotechnological foundations of this field to assist the reader in the comprehension and interpretation of the research involved in hair cell regeneration. Next, the author presents a review of stem…

  8. Centroacinar cells: At the center of pancreas regeneration.

    Beer, Rebecca L; Parsons, Michael J; Rovira, Meritxell

    2016-05-01

    The process of regeneration serves to heal injury by replacing missing cells. Understanding regeneration can help us replace cell populations lost during disease, such as the insulin-producing β cells lost in diabetic patients. Centroacinar cells (CACs) are a specialized ductal pancreatic cell type that act as progenitors to replace β cells in the zebrafish. However, whether CACs contribute to β-cell regeneration in adult mammals remains controversial. Here we review the current understanding of the role of CACs as endocrine progenitors during regeneration in zebrafish and mammals. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Engaging Stem Cells for Customized Tendon Regeneration

    Hatim Thaker

    2012-01-01

    Full Text Available The need for a consistent therapeutic approach to tendon injury repair is long overdue. Patients with tendon microtears or full ruptures are eligible for a wide range of invasive and non invasive interventions, often subjectively decided by the physician. Surgery produces the best outcomes, and while studies have been conducted to optimize graft constructs and to track outcomes, the data from these studies have been inconclusive on the whole. What has been established is a clear understanding of healthy tendon architecture and the inherent process of healing. With this knowledge, tissue regeneration efforts have achieved immense progress in scaffold design, cell line selection, and, more recently, the appropriate use of cytokines and growth factors. This paper evaluates the plasticity of bone-marrow-derived stem cells and the elasticity of recently developed biomaterials towards tendon regeneration efforts. Mesenchymal stem cells (MSCs, hematopoietic progenitor cells, and poly(1,8-octanediol co-citrate scaffolds (POC are discussed in the context of established grafting strategies. With POC scaffolds to cradle the growth of MSCs and hematopoietic progenitor cells, developing a fibroelastic network guided by cytokines and growth factors may contribute towards consistent graft constructs, enhanced functionality, and better patient outcomes.

  10. Hair cell regeneration in the avian auditory epithelium.

    Stone, Jennifer S; Cotanche, Douglas A

    2007-01-01

    Regeneration of sensory hair cells in the mature avian inner ear was first described just over 20 years ago. Since then, it has been shown that many other non-mammalian species either continually produce new hair cells or regenerate them in response to trauma. However, mammals exhibit limited hair cell regeneration, particularly in the auditory epithelium. In birds and other non-mammals, regenerated hair cells arise from adjacent non-sensory (supporting) cells. Hair cell regeneration was initially described as a proliferative response whereby supporting cells re-enter the mitotic cycle, forming daughter cells that differentiate into either hair cells or supporting cells and thereby restore cytoarchitecture and function in the sensory epithelium. However, further analyses of the avian auditory epithelium (and amphibian vestibular epithelium) revealed a second regenerative mechanism, direct transdifferentiation, during which supporting cells change their gene expression and convert into hair cells without dividing. In the chicken auditory epithelium, these two distinct mechanisms show unique spatial and temporal patterns, suggesting they are differentially regulated. Current efforts are aimed at identifying signals that maintain supporting cells in a quiescent state or direct them to undergo direct transdifferentiation or cell division. Here, we review current knowledge about supporting cell properties and discuss candidate signaling molecules for regulating supporting cell behavior, in quiescence and after damage. While significant advances have been made in understanding regeneration in non-mammals over the last 20 years, we have yet to determine why the mammalian auditory epithelium lacks the ability to regenerate hair cells spontaneously and whether it is even capable of significant regeneration under additional circumstances. The continued study of mechanisms controlling regeneration in the avian auditory epithelium may lead to strategies for inducing

  11. In vitro regeneration of kidney from pluripotent stem cells

    Osafune, Kenji, E-mail: osafu@cira.kyoto-u.ac.jp [Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan); JST Yamanaka iPS Cell Special Project, Japan Science and Technology Agency (JST), 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)

    2010-10-01

    Although renal transplantation has proved a successful treatment for the patients with end-stage renal failure, the therapy is hampered by the problem of serious shortage of donor organs. Regenerative medicine using stem cells, including cell transplantation therapy, needs to be developed to solve the problem. We previously identified the multipotent progenitor cells in the embryonic mouse kidney that can give rise to several kinds of epithelial cells found in adult kidney, such as glomerular podocytes and renal tubular epithelia. Establishing the method to generate the progenitors from human pluripotent stem cells that have the capacity to indefinitely proliferate in vitro is required for the development of kidney regeneration strategy. We review the current status of the research on the differentiation of pluripotent stem cells into renal lineages and describe cues to promote this research field.

  12. In vitro regeneration of kidney from pluripotent stem cells

    Osafune, Kenji

    2010-01-01

    Although renal transplantation has proved a successful treatment for the patients with end-stage renal failure, the therapy is hampered by the problem of serious shortage of donor organs. Regenerative medicine using stem cells, including cell transplantation therapy, needs to be developed to solve the problem. We previously identified the multipotent progenitor cells in the embryonic mouse kidney that can give rise to several kinds of epithelial cells found in adult kidney, such as glomerular podocytes and renal tubular epithelia. Establishing the method to generate the progenitors from human pluripotent stem cells that have the capacity to indefinitely proliferate in vitro is required for the development of kidney regeneration strategy. We review the current status of the research on the differentiation of pluripotent stem cells into renal lineages and describe cues to promote this research field.

  13. Composite cell sheet for periodontal regeneration: crosstalk between different types of MSCs in cell sheet facilitates complex periodontal-like tissue regeneration.

    Zhang, Hao; Liu, Shiyu; Zhu, Bin; Xu, Qiu; Ding, Yin; Jin, Yan

    2016-11-14

    Tissue-engineering strategies based on mesenchymal stem cells (MSCs) and cell sheets have been widely used for periodontal tissue regeneration. However, given the complexity in periodontal structure, the regeneration methods using a single species of MSC could not fulfill the requirement for periodontal regeneration. We researched the interaction between the periodontal ligament stem cells (PDLSCs) and jaw bone marrow-derived mesenchymal stem cells (JBMMSCs), and constructed a composite cell sheet comprising both of the above MSCs to regenerate complex periodontium-like structures in nude mice. Our results show that by co-culturing PDLSCs and JBMMSCs, the expressions of bone and extracellular matrix (ECM)-related genes and proteins were significantly improved in both MSCs. Further investigations showed that, compared to the cell sheet using PDLSCs or JBMMSCs, the composite stem cell sheet (CSCS), which comprises these two MSCs, expressed higher levels of bone- and ECM-related genes and proteins, and generated a composite structure more similar to the native periodontal tissue physiologically in vivo. In conclusion, our results demonstrate that the crosstalk between PDLSCs and JBMMSCs in cell sheets facilitate regeneration of complex periodontium-like structures, providing a promising new strategy for physiological and functional regeneration of periodontal tissue.

  14. Thermal regeneration of an electrochemical concentration cell

    Krumpelt, Michael; Bates, John K.

    1981-01-01

    A system and method for thermally regenerating an electrochemical concentration cell having first and second aluminum electrodes respectively positioned in contact with first and second electrolytes separated by an ion exchange member, the first and second electrolytes being composed of different concentrations of an ionic solvent and a salt, preferably an aluminum halide. The ionic solvent may be either organic or inorganic with a relatively low melting point, the ionic solvent and the salt form a complex wherein the free energy of formation of said complex is less than about -5 Kcal/mole. A distillation column using solar heat or low grade industrial waste heat receives the first and second electrolytes and thermally decomposes the salt-solvent complex to provide feed material for the two half cells.

  15. Repair and regeneration: opportunities for carcinogenesis from tissue stem cells

    Perryman, Scott V; Sylvester, Karl G

    2007-01-01

    This review will discuss the mechanisms of repair and regeneration in various tissue types and how dysregulation of these mechaisms may lead to cancer. Normal homeostasis involves a careful balance between cell loss and cell renewal. Stem and progenitor cells perform these biologic processes as the functional units of regeneration during both tissue homeostasis and repair. The concept of tissue stem cells capable of giving rise to all differentiated cells within a given tissue led to the conc...

  16. Fetal stem cells and skeletal muscle regeneration: a therapeutic approach

    Michela ePozzobon

    2014-08-01

    Full Text Available More than 40% of the body mass is represented by muscle tissue, which possesses the innate ability to regenerate after damage through the activation of muscle specific stem cell, namely satellite cells. Muscle diseases, in particular chronic degenerative state of skeletal muscle such as dystrophies, lead to a perturbation of the regenerative process, which causes the premature exhaustion of satellite cell reservoir due to continue cycles of degeneration/regeneration. Nowadays, the research is focused on different therapeutic approaches, ranging from gene and cell to pharmacological therapy, but still there is not a definitive cure in particular for genetic muscle disease. Taking this in mind, in this article we will give special consideration to muscle diseases and the use of fetal derived stem cells as new approach for therapy. Cells of fetal origin, from cord blood to placenta and amniotic fluid, can be easily obtained without ethical concern, expanded and differentiated in culture, and possess immunemodulatory properties. The in vivo approach in animal models can be helpful to study the mechanism underneath the operating principle of the stem cell reservoir, namely the niche, which holds great potential to understand the onset of muscle pathologies.

  17. Unique Aspects of Cryptochrome in Chronobiology and Metabolism, Pancreatic β-Cell Dysfunction, and Regeneration: Research into Cysteine414-Alanine Mutant CRY1

    Satoshi Okano

    2016-01-01

    Full Text Available Cryptochrome proteins (CRYs, which can bind noncovalently to cofactor (chromophore flavin adenine dinucleotide (FAD, occur widely among organisms. CRYs play indispensable roles in the generation of circadian rhythm in mammals. Transgenic mice (Tg mice, ubiquitously expressing mouse CRY1 having a mutation in which cysteine414 (the zinc-binding site of CRY1 being replaced with alanine, display unique phenotypes in their circadian rhythms. Moreover, male Tg mice exhibit symptoms of diabetes characterized by beta-cell dysfunction, resembling human maturity onset diabetes of the young (MODY. The lowered proliferation of β-cells is a primary cause of age-dependent β-cell loss. Furthermore, unusually enlarged duct-like structures developed prominently in the Tg mice pancreases. The duct-like structures contained insulin-positive cells, suggesting neogenesis of β-cells in the Tg mice. This review, based mainly on the author’s investigation of the unique features of Tg mice, presents reported results and recent findings related to molecular processes associated with mammalian cryptochromes, especially their involvement in the regulation of metabolism. New information is described with emphasis on the aspects of islet architecture, pancreatic β-cell dysfunction, and regeneration.

  18. β-Cell regeneration through the transdifferentiation of pancreatic cells: Pancreatic progenitor cells in the pancreas.

    Kim, Hyo-Sup; Lee, Moon-Kyu

    2016-05-01

    Pancreatic progenitor cell research has been in the spotlight, as these cells have the potential to replace pancreatic β-cells for the treatment of type 1 and 2 diabetic patients with the absence or reduction of pancreatic β-cells. During the past few decades, the successful treatment of diabetes through transplantation of the whole pancreas or isolated islets has nearly been achieved. However, novel sources of pancreatic islets or insulin-producing cells are required to provide sufficient amounts of donor tissues. To overcome this limitation, the use of pancreatic progenitor cells is gaining more attention. In particular, pancreatic exocrine cells, such as duct epithelial cells and acinar cells, are attractive candidates for β-cell regeneration because of their differentiation potential and pancreatic lineage characteristics. It has been assumed that β-cell neogenesis from pancreatic progenitor cells could occur in pancreatic ducts in the postnatal stage. Several studies have shown that insulin-producing cells can arise in the duct tissue of the adult pancreas. Acinar cells also might have the potential to differentiate into insulin-producing cells. The present review summarizes recent progress in research on the transdifferentiation of pancreatic exocrine cells into insulin-producing cells, especially duct and acinar cells.

  19. LSD1 is Required for Hair Cell Regeneration in Zebrafish.

    He, Yingzi; Tang, Dongmei; Cai, Chengfu; Chai, Renjie; Li, Huawei

    2016-05-01

    Lysine-specific demethylase 1 (LSD1/KDM1A) plays an important role in complex cellular processes such as differentiation, proliferation, apoptosis, and cell cycle progression. It has recently been demonstrated that during development, downregulation of LSD1 inhibits cell proliferation, modulates the expression of cell cycle regulators, and reduces hair cell formation in the zebrafish lateral line, which suggests that LSD1-mediated epigenetic regulation plays a key role in the development of hair cells. However, the role of LSD1 in hair cell regeneration after hair cell loss remains poorly understood. Here, we demonstrate the effect of LSD1 on hair cell regeneration following neomycin-induced hair cell loss. We show that the LSD1 inhibitor trans-2-phenylcyclopropylamine (2-PCPA) significantly decreases the regeneration of hair cells in zebrafish after neomycin damage. In addition, immunofluorescent staining demonstrates that 2-PCPA administration suppresses supporting cell proliferation and alters cell cycle progression. Finally, in situ hybridization shows that 2-PCPA significantly downregulates the expression of genes related to Wnt/β-catenin and Fgf activation. Altogether, our data suggest that downregulation of LSD1 significantly decreases hair cell regeneration after neomycin-induced hair cell loss through inactivation of the Wnt/β-catenin and Fgf signaling pathways. Thus, LSD1 plays a critical role in hair cell regeneration and might represent a novel biomarker and potential therapeutic approach for the treatment of hearing loss.

  20. Isolation, characterization, and differentiation of stem cells for cartilage regeneration.

    Beane, Olivia S; Darling, Eric M

    2012-10-01

    The goal of tissue engineering is to create a functional replacement for tissues damaged by injury or disease. In many cases, impaired tissues cannot provide viable cells, leading to the investigation of stem cells as a possible alternative. Cartilage, in particular, may benefit from the use of stem cells since the tissue has low cellularity and cannot effectively repair itself. To address this need, researchers are investigating the chondrogenic capabilities of several multipotent stem cell sources, including adult and extra-embryonic mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and induced pluripotent stem cells (iPSCs). Comparative studies indicate that each cell type has advantages and disadvantages, and while direct comparisons are difficult to make, published data suggest some sources may be more promising for cartilage regeneration than others. In this review, we identify current approaches for isolating and chondrogenically differentiating MSCs from bone marrow, fat, synovium, muscle, and peripheral blood, as well as cells from extra-embryonic tissues, ESCs, and iPSCs. Additionally, we assess chondrogenic induction with growth factors, identifying standard cocktails used for each stem cell type. Cell-only (pellet) and scaffold-based studies are also included, as is a discussion of in vivo results.

  1. The planarian flatworm: an in vivo model for stem cell biology and nervous system regeneration

    Luca Gentile

    2011-01-01

    Full Text Available Planarian flatworms are an exception among bilaterians in that they possess a large pool of adult stem cells that enables them to promptly regenerate any part of their body, including the brain. Although known for two centuries for their remarkable regenerative capabilities, planarians have only recently emerged as an attractive model for studying regeneration and stem cell biology. This revival is due in part to the availability of a sequenced genome and the development of new technologies, such as RNA interference and next-generation sequencing, which facilitate studies of planarian regeneration at the molecular level. Here, we highlight why planarians are an exciting tool in the study of regeneration and its underlying stem cell biology in vivo, and discuss the potential promises and current limitations of this model organism for stem cell research and regenerative medicine.

  2. Engineering Cell Fate for Tissue Regeneration by In Vivo Transdifferentiation.

    de Lázaro, I; Kostarelos, K

    2016-02-01

    Changes in cell identity occur in adult mammalian organisms but are rare and often linked to disease. Research in the last few decades has thrown light on how to manipulate cell fate, but the conversion of a particular cell type into another within a living organism (also termed in vivo transdifferentiation) has only been recently achieved in a limited number of tissues. Although the therapeutic promise of this strategy for tissue regeneration and repair is exciting, important efficacy and safety concerns will need to be addressed before it becomes a reality in the clinical practice. Here, we review the most relevant in vivo transdifferentiation studies in adult mammalian animal models, offering a critical assessment of this potentially powerful strategy for regenerative medicine.

  3. Dentin and dental pulp regeneration by the patient's endogenous cells.

    Kim, Sahng G; Zheng, Ying; Zhou, Jian; Chen, Mo; Embree, Mildred C; Song, Karen; Jiang, Nan; Mao, Jeremy J

    2013-03-01

    The goal of regenerative endodontics is to restore the functions of the dental pulp-dentin complex. Two approaches are being applied toward dental pulp-dentin regeneration: cell transplantation and cell homing. The majority of previous approaches are based on cell transplantation by delivering ex vivo cultivated cells toward dental pulp or dentin regeneration. Many hurdles limit the clinical translation of cell transplantation such as the difficulty of acquiring and isolating viable cells, uncertainty of what cells or what fractions of cells to use, excessive cost of cell manipulation and transportation, and the risk of immune rejection, pathogen transmission, and tumorigenesis in associated with ex vivo cell manipulation. In contrast, cell homing relies on induced chemotaxis of endogenous cells and therefore circumvents many of the difficulties that are associated with cell transplantation. An array of proteins, peptides, and chemical compounds that are yet to be identified may orchestrate endogenous cells to regenerate dental pulp-dentin complex. Both cell transplantation and cell homing are scientifically valid approaches; however, cell homing offers a number of advantages that are compatible with the development of clinical therapies for dental pulp-dentin regeneration.

  4. Stem cell death and survival in heart regeneration and repair.

    Abdelwahid, Eltyeb; Kalvelyte, Audrone; Stulpinas, Aurimas; de Carvalho, Katherine Athayde Teixeira; Guarita-Souza, Luiz Cesar; Foldes, Gabor

    2016-03-01

    Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.

  5. Endogenous Ion Dynamics in Cell Motility and Tissue Regeneration

    Özkucur, N; Perike, S; Epperlein, H H; Funk, R H W

    2011-01-01

    Directional cell migration is an essential process, including regeneration of tissues, wound healing, and embryonic development. Cells achieve persistent directional migration by polarizing the spatiotemporal components involved in the morphological polarity. Ion transporter proteins situated at the cell membrane generates small electric fields that can induce directional cell motility. Besides them, externally applied direct current electric fields induce similar kind of responses as cell orientation and directional migration. However, the bioelectric mechanisms that lead to cellular directedness are poorly understood. Therefore, understanding the bioelectric signaling cues can serve as a powerful modality in controlling the cell behaviour, which can contribute additional insights for development and regeneration.

  6. SENSORY HAIR CELL REGENERATION IN THE ZEBRAFISH LATERAL LINE

    Lush, Mark E.; Piotrowski, Tatjana

    2014-01-01

    Damage or destruction of sensory hair cells in the inner ear leads to hearing or balance deficits that can be debilitating, especially in older adults. Unfortunately, the damage is permanent, as regeneration of the inner ear sensory epithelia does not occur in mammals. Zebrafish and other non-mammalian vertebrates have the remarkable ability to regenerate sensory hair cells and understanding the molecular and cellular basis for this regenerative ability will hopefully aid us in designing ther...

  7. Stem Cells for Cardiac Regeneration by Cell Therapy and Myocardial Tissue Engineering

    Wu, Jun; Zeng, Faquan; Weisel, Richard D.; Li, Ren-Ke

    Congestive heart failure, which often occurs progressively following a myocardial infarction, is characterized by impaired myocardial perfusion, ventricular dilatation, and cardiac dysfunction. Novel treatments are required to reverse these effects - especially in older patients whose endogenous regenerative responses to currently available therapies are limited by age. This review explores the current state of research for two related approaches to cardiac regeneration: cell therapy and tissue engineering. First, to evaluate cell therapy, we review the effectiveness of various cell types for their ability to limit ventricular dilatation and promote functional recovery following implantation into a damaged heart. Next, to assess tissue engineering, we discuss the characteristics of several biomaterials for their potential to physically support the infarcted myocardium and promote implanted cell survival following cardiac injury. Finally, looking ahead, we present recent findings suggesting that hybrid constructs combining a biomaterial with stem and supporting cells may be the most effective approaches to cardiac regeneration.

  8. Plasticity of intestinal epithelial cells in regeneration and cancer

    Tetteh, Paul W.

    2015-01-01

    Cellular plasticity refers to the ability of a cell to change its fate or identity in response to external or intrinsic factors. Regeneration of the intestinal epithelium after injury is driven mainly by plasticity of crypt stem cells that can rapidly divide to replace all the lost cells. Stem cell

  9. Regeneration

    George A. Schier; Wayne D. Shepperd; John R. Jones

    1985-01-01

    There are basically two approaches to regenerating aspen stands-sexual reproduction using seed, or vegetative regeneration by root suckering. In the West, root suckering is the most practical method. The advantage of having an existing, well established root system capable of producing numerous root suckers easily outweighs natural or artificial reforestation in the...

  10. Live-cell imaging: new avenues to investigate retinal regeneration

    Manuela Lahne

    2017-01-01

    Full Text Available Sensing and responding to our environment requires functional neurons that act in concert. Neuronal cell loss resulting from degenerative diseases cannot be replaced in humans, causing a functional impairment to integrate and/or respond to sensory cues. In contrast, zebrafish (Danio rerio possess an endogenous capacity to regenerate lost neurons. Here, we will focus on the processes that lead to neuronal regeneration in the zebrafish retina. Dying retinal neurons release a damage signal, tumor necrosis factor α, which induces the resident radial glia, the Müller glia, to reprogram and re-enter the cell cycle. The Müller glia divide asymmetrically to produce a Müller glia that exits the cell cycle and a neuronal progenitor cell. The arising neuronal progenitor cells undergo several rounds of cell divisions before they migrate to the site of damage to differentiate into the neuronal cell types that were lost. Molecular and immunohistochemical studies have predominantly provided insight into the mechanisms that regulate retinal regeneration. However, many processes during retinal regeneration are dynamic and require live-cell imaging to fully discern the underlying mechanisms. Recently, a multiphoton imaging approach of adult zebrafish retinal cultures was developed. We will discuss the use of live-cell imaging, the currently available tools and those that need to be developed to advance our knowledge on major open questions in the field of retinal regeneration.

  11. Mesenchymal stem cell-mediated functional tooth regeneration in swine.

    Wataru Sonoyama

    2006-12-01

    Full Text Available Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla. Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

  12. Stem cell therapy for intervertebral disc regeneration: review article

    Mohsen Sheykhhasan

    2017-02-01

    Full Text Available Intervertebral disks (IVD acts as shock absorber between each of the vertebrae in the spinal column by keeping the vertebrae separated when the shock caused by the action. They also serve to protect the nerves that run down the middle of the spine and intervertebral disks. The disks are made of fibrocartilaginous material. The outside of the disk is made of a strong material called the annulus fibrosus. Inside this protective covering is a jelly-like substance known as mucoprotein gel. This interior is known as the nucleus pulposus. The nucleus pulposus consists of large vacuolated notochord cells, small chondrocyte-like cells, collagen fibrils, and aggrecan, a proteoglycan that aggregates by binding to hyaluronan. Attached to each aggrecan molecule are glycosaminoglycan (GAG chains of chondroitin sulfate and keratan sulfate. Intervertebral disks degeneration is frequently associated with low back and neck pain, which accounts as a disability. Despite the known outcomes of the Intervertebral disks degeneration cascade, the treatment of IVD degeneration is limited in that available conservative and surgical treatments do not reverse the pathology or restore the IVD tissue. Regenerative medicine for IVD degeneration, by injection of Intervertebral disks cells, chondrocytes or stem cells, has been extensively studied in the past decade in various animal models of induced IVD degeneration, and has progressed to clinical trials in the treatment of various spinal disease. Despite preliminary results showing positive effects of cell-injection strategies for IVD regeneration, detailed basic research on Intervertebral disks cells and their niche demonstrates that transplanted cells are unable to survive and adapt in the avascular niche of the IVD. For this therapeutic strategy to succeed, the indications for its use and the patients who would benefit need to be better defined. To surmount these obstacles, the solution will be identified only by focused

  13. Spontaneous hair cell regeneration in the mouse utricle following gentamicin ototoxicity.

    Kawamoto, Kohei; Izumikawa, Masahiko; Beyer, Lisa A; Atkin, Graham M; Raphael, Yehoash

    2009-01-01

    Whereas most epithelial tissues turn-over and regenerate after a traumatic lesion, this restorative ability is diminished in the sensory epithelia of the inner ear; it is absent in the cochlea and exists only in a limited capacity in the vestibular epithelium. The extent of regeneration in vestibular hair cells has been characterized for several mammalian species including guinea pig, rat, and chinchilla, but not yet in mouse. As the fundamental model species for investigating hereditary disease, the mouse can be studied using a wide variety of genetic and molecular tools. To design a mouse model for vestibular hair cell regeneration research, an aminoglycoside-induced method of complete hair cell elimination was developed in our lab and applied to the murine utricle. Loss of utricular hair cells was observed using scanning electron microscopy, and corroborated by a loss of fluorescent signal in utricles from transgenic mice with GFP-positive hair cells. Regenerative capability was characterized at several time points up to six months following insult. Using scanning electron microscopy, we observed that as early as two weeks after insult, a few immature hair cells, demonstrating the characteristic immature morphology indicative of regeneration, could be seen in the utricle. As time progressed, larger numbers of immature hair cells could be seen along with some mature cells resembling surface morphology of type II hair cells. By six months post-lesion, numerous regenerated hair cells were present in the utricle, however, neither their number nor their appearance was normal. A BrdU assay suggested that at least some of the regeneration of mouse vestibular hair cells involved mitosis. Our results demonstrate that the vestibular sensory epithelium in mice can spontaneously regenerate, elucidate the time course of this process, and identify involvement of mitosis in some cases. These data establish a road map of the murine vestibular regenerative process, which can be

  14. Development and regeneration of vestibular hair cells in mammals.

    Burns, Joseph C; Stone, Jennifer S

    2017-05-01

    Vestibular sensation is essential for gaze stabilization, balance, and perception of gravity. The vestibular receptors in mammals, Type I and Type II hair cells, are located in five small organs in the inner ear. Damage to hair cells and their innervating neurons can cause crippling symptoms such as vertigo, visual field oscillation, and imbalance. In adult rodents, some Type II hair cells are regenerated and become re-innervated after damage, presenting opportunities for restoring vestibular function after hair cell damage. This article reviews features of vestibular sensory cells in mammals, including their basic properties, how they develop, and how they are replaced after damage. We discuss molecules that control vestibular hair cell regeneration and highlight areas in which our understanding of development and regeneration needs to be deepened. Copyright © 2016 Elsevier Ltd. All rights reserved.

  15. In situ tissue regeneration: chemoattractants for endogenous stem cell recruitment.

    Vanden Berg-Foels, Wendy S

    2014-02-01

    Tissue engineering uses cells, signaling molecules, and/or biomaterials to regenerate injured or diseased tissues. Ex vivo expanded mesenchymal stem cells (MSC) have long been a cornerstone of regeneration therapies; however, drawbacks that include altered signaling responses and reduced homing capacity have prompted investigation of regeneration based on endogenous MSC recruitment. Recent successful proof-of-concept studies have further motivated endogenous MSC recruitment-based approaches. Stem cell migration is required for morphogenesis and organogenesis during development and for tissue maintenance and injury repair in adults. A biomimetic approach to in situ tissue regeneration by endogenous MSC requires the orchestration of three main stages: MSC recruitment, MSC differentiation, and neotissue maturation. The first stage must result in recruitment of a sufficient number of MSC, capable of effecting regeneration, to the injured or diseased tissue. One of the challenges for engineering endogenous MSC recruitment is the selection of effective chemoattractant(s). The objective of this review is to synthesize and evaluate evidence of recruitment efficacy by reported chemoattractants, including growth factors, chemokines, and other more recently appreciated MSC chemoattractants. The influence of MSC tissue sources, cell culture methods, and the in vitro and in vivo environments is discussed. This growing body of knowledge will serve as a basis for the rational design of regenerative therapies based on endogenous MSC recruitment. Successful endogenous MSC recruitment is the first step of successful tissue regeneration.

  16. The Urodele Limb Regeneration Blastema: The Cell Potential

    Kenyon S. Tweedell

    2010-01-01

    Full Text Available The developmental potential of the limb regeneration blastema, a mass of mesenchymal cells of mixed origins, was once considered as being pluripotent, capable of forming all cell types. Now evidence asserts that the blastema is a heterogeneous mixture of progenitor cells derived from tissues of the amputation site, with limited developmental potential, plus various stem cells with multipotent abilities. Many specialized cells, bone, cartilage, muscle, and Schwann cells, at the injury site undergo dedifferentiation to a progenitor state and maintain their cell lineage as they redifferentiate in the regenerate. Muscle satellite reserve stem cells that are active in repair of injured muscle may also dedifferentiate and contribute new muscle cells to the limb blastema. Other cells from the dermis act as multipotent stem cells that replenish dermal fibroblasts and differentiate into cartilage. The blastema primordium is a self-organized, equipotential system, but at the cellular level can compensate for specific cell loss. It is able to induce dedifferentiation of introduced exogenous cells and such cells may be transformed into new cell types. Indigenous cells of the blastema associated with amputated tissues may also transform or possibly transdifferentiate into new cell types. The blastema is a microenvironment that enables dedifferentiation, redifferentiation, transdifferentiation, and stem cell activation, leading to progenitor cells of the limb regenerate.

  17. Guided genetic screen to identify genes essential in the regeneration of hair cells and other tissues.

    Pei, Wuhong; Xu, Lisha; Huang, Sunny C; Pettie, Kade; Idol, Jennifer; Rissone, Alberto; Jimenez, Erin; Sinclair, Jason W; Slevin, Claire; Varshney, Gaurav K; Jones, MaryPat; Carrington, Blake; Bishop, Kevin; Huang, Haigen; Sood, Raman; Lin, Shuo; Burgess, Shawn M

    2018-01-01

    Regenerative medicine holds great promise for both degenerative diseases and traumatic tissue injury which represent significant challenges to the health care system. Hearing loss, which affects hundreds of millions of people worldwide, is caused primarily by a permanent loss of the mechanosensory receptors of the inner ear known as hair cells. This failure to regenerate hair cells after loss is limited to mammals, while all other non-mammalian vertebrates tested were able to completely regenerate these mechanosensory receptors after injury. To understand the mechanism of hair cell regeneration and its association with regeneration of other tissues, we performed a guided mutagenesis screen using zebrafish lateral line hair cells as a screening platform to identify genes that are essential for hair cell regeneration, and further investigated how genes essential for hair cell regeneration were involved in the regeneration of other tissues. We created genetic mutations either by retroviral insertion or CRISPR/Cas9 approaches, and developed a high-throughput screening pipeline for analyzing hair cell development and regeneration. We screened 254 gene mutations and identified 7 genes specifically affecting hair cell regeneration. These hair cell regeneration genes fell into distinct and somewhat surprising functional categories. By examining the regeneration of caudal fin and liver, we found these hair cell regeneration genes often also affected other types of tissue regeneration. Therefore, our results demonstrate guided screening is an effective approach to discover regeneration candidates, and hair cell regeneration is associated with other tissue regeneration.

  18. Lung Regeneration: Endogenous and Exogenous Stem Cell Mediated Therapeutic Approaches.

    Akram, Khondoker M; Patel, Neil; Spiteri, Monica A; Forsyth, Nicholas R

    2016-01-19

    The tissue turnover of unperturbed adult lung is remarkably slow. However, after injury or insult, a specialised group of facultative lung progenitors become activated to replenish damaged tissue through a reparative process called regeneration. Disruption in this process results in healing by fibrosis causing aberrant lung remodelling and organ dysfunction. Post-insult failure of regeneration leads to various incurable lung diseases including chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. Therefore, identification of true endogenous lung progenitors/stem cells, and their regenerative pathway are crucial for next-generation therapeutic development. Recent studies provide exciting and novel insights into postnatal lung development and post-injury lung regeneration by native lung progenitors. Furthermore, exogenous application of bone marrow stem cells, embryonic stem cells and inducible pluripotent stem cells (iPSC) show evidences of their regenerative capacity in the repair of injured and diseased lungs. With the advent of modern tissue engineering techniques, whole lung regeneration in the lab using de-cellularised tissue scaffold and stem cells is now becoming reality. In this review, we will highlight the advancement of our understanding in lung regeneration and development of stem cell mediated therapeutic strategies in combating incurable lung diseases.

  19. Stem cells applications in bone and tooth repair and regeneration: New insights, tools, and hopes.

    Abdel Meguid, Eiman; Ke, Yuehai; Ji, Junfeng; El-Hashash, Ahmed H K

    2018-03-01

    The exploration of stem and progenitor cells holds promise for advancing our understanding of the biology of tissue repair and regeneration mechanisms after injury. This will also help in the future use of stem cell therapy for the development of regenerative medicine approaches for the treatment of different tissue-species defects or disorders such as bone, cartilages, and tooth defects or disorders. Bone is a specialized connective tissue, with mineralized extracellular components that provide bones with both strength and rigidity, and thus enable bones to function in body mechanical supports and necessary locomotion process. New insights have been added to the use of different types of stem cells in bone and tooth defects over the last few years. In this concise review, we briefly describe bone structure as well as summarize recent research progress and accumulated information regarding the osteogenic differentiation of stem cells, as well as stem cell contributions to bone repair/regeneration, bone defects or disorders, and both restoration and regeneration of bones and cartilages. We also discuss advances in the osteogenic differentiation and bone regeneration of dental and periodontal stem cells as well as in stem cell contributions to dentine regeneration and tooth engineering. © 2017 Wiley Periodicals, Inc.

  20. Chemical strategies for pancreatic β cell differentiation, reprogramming, and regeneration.

    Ma, Xiaojie; Zhu, Saiyong

    2017-04-01

    Generation of unlimited functional pancreatic β cells is critical for the study of pancreatic biology and treatment of diabetes mellitus. Recent advances have suggested several promising directions, including directed differentiation of pancreatic β cells from pluripotent stem cells, reprogramming of pancreatic β cells from other types of somatic cells, and stimulated proliferation and enhanced functions of existing pancreatic β cells. Small molecules are useful in generating unlimited numbers of functional pancreatic cells in vitro and could be further developed as drugs to stimulate endogenous pancreatic regeneration. Here, we provide an updated summary of recent major achievements in pancreatic β cell differentiation, reprogramming, proliferation, and function. These studies will eventually lead to significant advances in the field of pancreatic biology and regeneration. © The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Meniscus repair and regeneration: review on current methods and research potential

    C Scotti

    2013-01-01

    Full Text Available Meniscus regeneration is an unsolved clinical challenge. Despite the wide acceptance of the degenerative consequences of meniscectomy, no surgical procedure has succeeded to date in regenerating a functional and long-lasting meniscal fibrocartilage. Research proposed a number of experimental approaches encompassing all the typical strategies of regenerative medicine: cell-free scaffolds, gene therapy, intra-articular delivery of progenitor cells, biological glues for enhanced bonding of reparable tears, partial and total tissue engineered meniscus replacement. None of these approaches has been completely successful and can be considered suitable for all patients, as meniscal tears require specific and patient-related treatments depending on the size and type of lesion. Recent advances in cell biology, biomaterial science and bioengineering (e.g., bioreactors have now the potential to drive meniscus regeneration into a series of clinically relevant strategies. In this tutorial paper, the clinical need for meniscus regeneration strategies will be explained, and past and current experimental studies on meniscus regeneration will be reported.

  2. Müller stem cell dependent retinal regeneration.

    Chohan, Annu; Singh, Usha; Kumar, Atul; Kaur, Jasbir

    2017-01-01

    Müller Stem cells to treat ocular diseases has triggered enthusiasm across all medical and scientific communities. Recent development in the field of stem cells has widened the prospects of applying cell based therapies to regenerate ocular tissues that have been irreversibly damaged by disease or injury. Ocular tissues such as the lens and the retina are now known to possess cell having remarkable regenerative abilities. Recent studies have shown that the Müller glia, a cell found in all vertebrate retinas, is the primary source of new neurons, and therefore are considered as the cellular basis for retinal regeneration in mammalian retinas. Here, we review the current status of retinal regeneration of the human eye by Müller stem cells. This review elucidates the current status of retinal regeneration by Müller stem cells, along with major retinal degenerative diseases where these stem cells play regenerative role in retinal repair and replacement. Copyright © 2016. Published by Elsevier B.V.

  3. Arrhythmogenic consequences of stem cell therapy for cardiac regeneration

    Smit, N.W.

    2018-01-01

    A third of the patients that survive a myocardial infarction develop heart failure for which no effective treatment exists. Stem cell therapy could be a possible solution by regeneration of the myocardium. However, the possible electrophysiological effects of interactions between stem cells and

  4. Magnetic field exposure stiffens regenerating plant protoplast cell walls.

    Haneda, Toshihiko; Fujimura, Yuu; Iino, Masaaki

    2006-02-01

    Single suspension-cultured plant cells (Catharanthus roseus) and their protoplasts were anchored to a glass plate and exposed to a magnetic field of 302 +/- 8 mT for several hours. Compression forces required to produce constant cell deformation were measured parallel to the magnetic field by means of a cantilever-type force sensor. Exposure of intact cells to the magnetic field did not result in any changes within experimental error, while exposure of regenerating protoplasts significantly increased the measured forces and stiffened regenerating protoplasts. The diameters of intact cells or regenerating protoplasts were not changed after exposure to the magnetic field. Measured forces for regenerating protoplasts with and without exposure to the magnetic field increased linearly with incubation time, with these forces being divided into components based on the elasticity of synthesized cell walls and cytoplasm. Cell wall synthesis was also measured using a cell wall-specific fluorescent dye, and no changes were noted after exposure to the magnetic field. Analysis suggested that exposure to the magnetic field roughly tripled the Young's modulus of the newly synthesized cell wall without any lag.

  5. Enhanced regeneration of degraded polymer solar cells by thermal annealing

    Kumar, Pankaj, E-mail: pankaj@mail.nplindia.ernet.in [CSIR-National Physical Laboratory, Dr. K. S. Krishnan Marg, New Delhi 110012 (India); Centre for Organic Electronics, Physics, University of Newcastle, Callaghan NSW-2308 (Australia); Bilen, Chhinder; Zhou, Xiaojing; Belcher, Warwick J.; Dastoor, Paul C., E-mail: Paul.Dastoor@newcastle.edu.au [Centre for Organic Electronics, Physics, University of Newcastle, Callaghan NSW-2308 (Australia); Feron, Krishna [Centre for Organic Electronics, Physics, University of Newcastle, Callaghan NSW-2308 (Australia); CSIRO Energy Technology, P. O. Box 330, Newcastle NSW 2300 (Australia)

    2014-05-12

    The degradation and thermal regeneration of poly(3-hexylethiophene) (P3HT):[6,6]-phenyl-C{sub 61}-butyric acid methyl ester (PCBM) and P3HT:indene-C{sub 60} bisadduct (ICBA) polymer solar cells, with Ca/Al and Ca/Ag cathodes and indium tin oxide/poly(ethylene-dioxythiophene):polystyrene sulfonate anode have been investigated. Degradation occurs via a combination of three primary pathways: (1) cathodic oxidation, (2) active layer phase segregation, and (3) anodic diffusion. Fully degraded devices were subjected to thermal annealing under inert atmosphere. Degraded solar cells possessing Ca/Ag electrodes were observed to regenerate their performance, whereas solar cells having Ca/Al electrodes exhibited no significant regeneration of device characteristics after thermal annealing. Moreover, the solar cells with a P3HT:ICBA active layer exhibited enhanced regeneration compared to P3HT:PCBM active layer devices as a result of reduced changes to the active layer morphology. Devices combining a Ca/Ag cathode and P3HT:ICBA active layer demonstrated ∼50% performance restoration over several degradation/regeneration cycles.

  6. Enhanced regeneration of degraded polymer solar cells by thermal annealing

    Kumar, Pankaj; Bilen, Chhinder; Zhou, Xiaojing; Belcher, Warwick J.; Dastoor, Paul C.; Feron, Krishna

    2014-01-01

    The degradation and thermal regeneration of poly(3-hexylethiophene) (P3HT):[6,6]-phenyl-C 61 -butyric acid methyl ester (PCBM) and P3HT:indene-C 60 bisadduct (ICBA) polymer solar cells, with Ca/Al and Ca/Ag cathodes and indium tin oxide/poly(ethylene-dioxythiophene):polystyrene sulfonate anode have been investigated. Degradation occurs via a combination of three primary pathways: (1) cathodic oxidation, (2) active layer phase segregation, and (3) anodic diffusion. Fully degraded devices were subjected to thermal annealing under inert atmosphere. Degraded solar cells possessing Ca/Ag electrodes were observed to regenerate their performance, whereas solar cells having Ca/Al electrodes exhibited no significant regeneration of device characteristics after thermal annealing. Moreover, the solar cells with a P3HT:ICBA active layer exhibited enhanced regeneration compared to P3HT:PCBM active layer devices as a result of reduced changes to the active layer morphology. Devices combining a Ca/Ag cathode and P3HT:ICBA active layer demonstrated ∼50% performance restoration over several degradation/regeneration cycles

  7. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy

    Patrizia Pessina

    2015-06-01

    Full Text Available Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD, skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.

  8. Human airway xenograft models of epithelial cell regeneration

    Puchelle Edith

    2000-10-01

    Full Text Available Abstract Regeneration and restoration of the airway epithelium after mechanical, viral or bacterial injury have a determinant role in the evolution of numerous respiratory diseases such as chronic bronchitis, asthma and cystic fibrosis. The study in vivo of epithelial regeneration in animal models has shown that airway epithelial cells are able to dedifferentiate, spread, migrate over the denuded basement membrane and progressively redifferentiate to restore a functional respiratory epithelium after several weeks. Recently, human tracheal xenografts have been developed in immunodeficient severe combined immunodeficiency (SCID and nude mice. In this review we recall that human airway cells implanted in such conditioned host grafts can regenerate a well-differentiated and functional human epithelium; we stress the interest in these humanized mice in assaying candidate progenitor and stem cells of the human airway mucosa.

  9. Cell-Based Meniscus Repair and Regeneration: At the Brink of Clinical Translation?

    Korpershoek, Jasmijn V.; de Windt, Tommy S.; Hagmeijer, Michella H.; Vonk, Lucienne A.; Saris, Daniel B. F.

    2017-01-01

    Background: Meniscus damage can be caused by trauma or degeneration and is therefore common among patients of all ages. Repair or regeneration of the menisci could be of great importance not only for pain relief or regaining function but also to prevent degenerative disease and osteoarthritis. Current treatment does not offer consistent long-term improvement. Although preclinical research focusing on augmentation of meniscal tear repair and regeneration after meniscectomy is encouraging, clinical translation remains difficult. Purpose: To systematically evaluate the literature on in vivo meniscus regeneration and explore the optimal cell sources and conditions for clinical translation. We aimed at thorough evaluation of current evidence as well as clarifying the challenges for future preclinical and clinical studies. Study Design: Systematic review. Methods: A search was conducted using the electronic databases of MEDLINE, Embase, and the Cochrane Collaboration. Search terms included meniscus, regeneration, and cell-based. Results: After screening 81 articles based on title and abstract, 51 articles on in vivo meniscus regeneration could be included; 2 additional articles were identified from the references. Repair and regeneration of the meniscus has been described by intra-articular injection of multipotent mesenchymal stromal (stem) cells from adipose tissue, bone marrow, synovium, or meniscus or the use of these cell types in combination with implantable or injectable scaffolds. The use of fibrochondrocytes, chondrocytes, and transfected myoblasts for meniscus repair and regeneration is limited to the combination with different scaffolds. The comparative in vitro and in vivo studies mentioned in this review indicate that the use of allogeneic cells is as successful as the use of autologous cells. In addition, the implantation or injection of cell-seeded scaffolds increased tissue regeneration and led to better structural organization compared with scaffold

  10. Stem cell regenerative potential combined with nanotechnology and tissue engineering for myocardial regeneration.

    Calin, Manuela; Stan, Daniela; Simion, Viorel

    2013-07-01

    The stem cell-based therapy for post-infarction myocardial regeneration has been introduced more than a decade ago, but the functional improvement obtained is limited due to the poor retention and short survival rate of transplanted cells into the damaged myocardium. More recently, the emerging nanotechnology concepts for advanced diagnostics and therapy provide promising opportunities of using stem cells for myocardial regeneration. In this paper will be provided an overview of the use of nanotechnology approaches in stem cell research for: 1) cell labeling to track the distribution of stem cells after transplantation, 2) nanoparticle-mediated gene delivery to stem cells to promote their homing, engraftment, survival and differentiation in the ischemic myocardium and 3) obtaining of bio-inspired materials to provide suitable myocardial scaffolds for delivery of stem cells or stem cell-derived factors.

  11. Mechanisms of pancreatic beta-cell growth and regeneration

    Nielsen, Jens Høiriis

    1989-01-01

    Information about the mechanism of beta-cell growth and regeneration may be obtained by studies of insulinoma cells. In the present study the growth and function of the rat insulinoma cell lines RINm5F and 5AH were evaluated by addition of serum, hormones, and growth factors. It was found...... of insulin mRNA content showed that the insulinoma cells only contained about 2% of that of normal rat beta-cells. These results are discussed in relation to the role of growth factors, oncogenes, and differentiation in the growth and regeneration of beta-cells....... that transferrin is the only obligatory factor whereas growth hormone, epidermal growth factor, fibroblast growth factor, and TRH had modulating effects. A heat-labile heparin binding serum factor which stimulated thymidine incorporation but not cell proliferation was demonstrated in human serum. Measurements...

  12. The muscle stem cell niche : regulation of satellite cells during regeneration

    Boonen, K.J.M.; Post, M.J.

    2008-01-01

    Satellite cells are considered to be adult skeletal muscle stem cells. Their ability to regenerate large muscle defects is highly dependent on their specific niche. When these cells are cultured in vitro, the loss of this niche leads to a loss of proliferative capacity and defective regeneration

  13. Cellular Mechanisms of Liver Regeneration and Cell-Based Therapies of Liver Diseases

    Irina V. Kholodenko

    2017-01-01

    Full Text Available The emerging field of regenerative medicine offers innovative methods of cell therapy and tissue/organ engineering as a novel approach to liver disease treatment. The ultimate scientific foundation of both cell therapy of liver diseases and liver tissue and organ engineering is delivered by the in-depth studies of the cellular and molecular mechanisms of liver regeneration. The cellular mechanisms of the homeostatic and injury-induced liver regeneration are unique. Restoration of the mass of liver parenchyma is achieved by compensatory hypertrophy and hyperplasia of the differentiated parenchymal cells, hepatocytes, while expansion and differentiation of the resident stem/progenitor cells play a minor or negligible role. Participation of blood-borne cells of the bone marrow origin in liver parenchyma regeneration has been proven but does not exceed 1-2% of newly formed hepatocytes. Liver regeneration is activated spontaneously after injury and can be further stimulated by cell therapy with hepatocytes, hematopoietic stem cells, or mesenchymal stem cells. Further studies aimed at improving the outcomes of cell therapy of liver diseases are underway. In case of liver failure, transplantation of engineered liver can become the best option in the foreseeable future. Engineering of a transplantable liver or its major part is an enormous challenge, but rapid progress in induced pluripotency, tissue engineering, and bioprinting research shows that it may be doable.

  14. Inexhaustible hair-cell regeneration in young and aged zebrafish

    Filipe Pinto-Teixeira

    2015-07-01

    Full Text Available Animals have evolved two general strategies to counter injury and maintain physiological function. The most prevalent is protection by isolating vital organs into body cavities. However, protection is not optimal for sensory systems because their external components need to be exposed to the environment to fulfill their receptive function. Thus, a common strategy to maintain sensory abilities against persistent environmental insult involves repair and regeneration. However, whether age or frequent injuries affect the regenerative capacity of sensory organs remains unknown. We have found that neuromasts of the zebrafish lateral line regenerate mechanosensory hair cells after recurrent severe injuries and in adulthood. Moreover, neuromasts can reverse transient imbalances of Notch signaling that result in defective organ proportions during repair. Our results reveal inextinguishable hair-cell regeneration in the lateral line, and suggest that the neuromast epithelium is formed by plastic territories that are maintained by continuous intercellular communication.

  15. Stem cell plasticity enables hair regeneration following Lgr5+ cell loss.

    Hoeck, Joerg D; Biehs, Brian; Kurtova, Antonina V; Kljavin, Noelyn M; de Sousa E Melo, Felipe; Alicke, Bruno; Koeppen, Hartmut; Modrusan, Zora; Piskol, Robert; de Sauvage, Frederic J

    2017-06-01

    Under injury conditions, dedicated stem cell populations govern tissue regeneration. However, the molecular mechanisms that induce stem cell regeneration and enable plasticity are poorly understood. Here, we investigate stem cell recovery in the context of the hair follicle to understand how two molecularly distinct stem cell populations are integrated. Utilizing diphtheria-toxin-mediated cell ablation of Lgr5 + (leucine-rich repeat-containing G-protein-coupled receptor 5) stem cells, we show that killing of Lgr5 + cells in mice abrogates hair regeneration but this is reversible. During recovery, CD34 + (CD34 antigen) stem cells activate inflammatory response programs and start dividing. Pharmacological attenuation of inflammation inhibits CD34 + cell proliferation. Subsequently, the Wnt pathway controls the recovery of Lgr5 + cells and inhibition of Wnt signalling prevents Lgr5 + cell and hair germ recovery. Thus, our study uncovers a compensatory relationship between two stem cell populations and the underlying molecular mechanisms that enable hair follicle regeneration.

  16. LIVER AND BONE MARROW STEM/PROGENITOR CELLS AS REGULATORS OF REPARATIVE REGENERATION OF DAMAGED LIVER

    А. V. Lundup

    2010-01-01

    Full Text Available In this review the modern information about effectiveness of liver insufficiency treatment by stem/ progenitor cells of liver (oval cells and bone marrow (hemopoietic cells and mesenchymal cells was presented. It is shown that medical action of these cells is referred on normalization of liver cell interaction and reorganization of processes of a reparative regeneration in damaged liver. It is believed that application of mesenchymal stromal cells from an autological bone marrow is the most perspective strategy. However, for definitive judgement about regenerative possibilities of the autological bone marrow cells it is necessary to carry out large-scale double blind clinical researches

  17. Designing the stem cell microenvironment for guided connective tissue regeneration.

    Bogdanowicz, Danielle R; Lu, Helen H

    2017-12-01

    Adult mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine because of their ability to self-renew and their capacity for multilineage differentiation and tissue regeneration. For connective tissues, such as ligaments or tendons, MSCs are vital to the modulation of the inflammatory response following acute injury while also interacting with resident fibroblasts to promote cell proliferation and matrix synthesis. To date, MSC injection for connective tissue repair has yielded mixed results in vivo, likely due to a lack of appropriate environmental cues to effectively control MSC response and promote tissue healing instead of scar formation. In healthy tissues, stem cells reside within a complex microenvironment comprising cellular, structural, and signaling cues that collectively maintain stemness and modulate tissue homeostasis. Changes to the microenvironment following injury regulate stem cell differentiation, trophic signaling, and tissue healing. Here, we focus on models of the stem cell microenvironment that are used to elucidate the mechanisms of stem cell regulation and inspire functional approaches to tissue regeneration. Recent studies in this frontier area are highlighted, focusing on how microenvironmental cues modulate MSC response following connective tissue injury and, more importantly, how this unique cell environment can be programmed for stem cell-guided tissue regeneration. © 2017 New York Academy of Sciences.

  18. Layer-by-Layer Bioprinting of Stem Cells for Retinal Tissue Regeneration

    2016-12-01

    Precision Tissue Models”, Distinguished Seminar, Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, University of...in vitro drug screening and potential in vivo retinal neuron repair. The expansion of ganglion cells is tightly related to the spatial arrangement of...AWARD NUMBER: W81XWH-14-1-0522 TITLE: Layer-by-Layer Bioprinting of Stem Cells for Retinal Tissue Regeneration PRINCIPAL INVESTIGATOR

  19. Pancreatic β-cell regeneration: Facultative or dedicated progenitors?

    Afelik, Solomon; Rovira, Meritxell

    2017-04-15

    The adult pancreas is only capable of limited regeneration. Unlike highly regenerative tissues such as the skin, intestinal crypts and hematopoietic system, no dedicated adult stem cells or stem cell niche have so far been identified within the adult pancreas. New β cells have been shown to form in the adult pancreas, in response to high physiological demand or experimental β-cell ablation, mostly by replication of existing β cells. The possibility that new β cells are formed from other sources is currently a point of major controversy. Under particular injury conditions, fully differentiated pancreatic duct and acinar cells have been shown to dedifferentiate into a progenitor-like state, however the extent, to which ductal, acinar or other endocrine cells contribute to restoring pancreatic β-cell mass remains to be resolved. In this review we focus on regenerative events in the pancreas with emphasis on the restoration of β-cell mass. We present an overview of regenerative responses noted within the different pancreatic lineages, following injury. We also highlight the intrinsic plasticity of the adult pancreas that allows for inter-conversion of fully differentiated pancreatic lineages through manipulation of few genes or growth factors. Taken together, evidence from a number of studies suggest that differentiated pancreatic lineages could act as facultative progenitor cells, but the extent to which these contribute to β-cell regeneration in vivo is still a matter of contention. Copyright © 2016. Published by Elsevier B.V.

  20. Increase of corneal epithelium cell radioresistance during regeneration

    Popova, M.F.; Bulyakova, N.V.; Azarova, V.S.

    1985-01-01

    A comparative study of the radiosensitivity of the normal and regenerating cornea epithelium of C 57 Bl mice was performed on the cellular level, the duration of the cell cycle being taken into account. Criteria of radiation injuries were the number of chromosome aberrations, mitotic index and duration of mitotic block. The anterior part of the head was irradiated singly with 1.75, 3.5 or 7.0 Gy and also repeatedly 3.5 + 3.5 at a 24-hours interval. The corneas were fixed 2, 4, 6, 12, 24, 48, 72 and 96 hours after irradiation. In all cases of irradiated mice the regenerating epithelium showed a shorter mitotic block and significantly lower cytogenetic injury as compared with the controls. Effects of fractionated irradiation were only shown in the regenerating epithelium. The results obtained indicate that regenerating epithelium cells of the cornea are significantly more radioresistant than normal epithelium due to activation of post-radiation recovery, and also, possibly, due to an increase in the content of endogenous radioprotectors. (author)

  1. [Regeneration of the ciliary beat of human ciliated cells].

    Wolf, G; Koidl, B; Pelzmann, B

    1991-10-01

    The influence of an isotonic, alkaline saline solution (diluted "Emser Sole" or brine from the spa of Bad Ems) on the ciliary beat of isolated cultured human ciliated cells of the upper respiratory tract was investigated. The ciliary beat was observed via an inverted phase contrast microscope (Zeiss Axiomat IDPC) and measured microphotometrically under physiological conditions and after the damaging influence of 1% propanal solution. Under physiological conditions the saline solution had a positive, although statistically not significant influence on the frequency of the ciliary beat. After damage of the cultivated cells by 1% propanal solution, the saline solution had a significant better influence on the regeneration of the cultured cells than a physiological sodium chloride solution. It is concluded that diluted brine from Bad Ems has a positive effect on the ciliary beat of the respiratory epithelium and accelerates its regeneration after damage by viral and bacterial infections, surgery or inhaled noxae.

  2. Regeneration of stem-cells in intestinal epithelium after irradiation

    Hendry, J.H.

    1979-01-01

    Stem-cells can be defined as pluripotent progenitor cells, capable of both self-renewal and differentitation into all the functional end-cells typical of that cell family. Intestinal crypts contain population of cells which is capable of a) self-renewal following the severe depletion after radiation injury, b) replacing all other cypt cell types, and c) regeneration following repeated depletion (in colon). These are the properties of stem cells. Most measurements of the rate of regeneration of these cells following the severe depletion by radiation have been made by employing large test dose at increasing times. Such measurements have produced widely differing rates of increase in the survival under the test dose, from 4 hours (macrocolonies in jejunum) to 43 hours (microcolonies in stomach). In other tissues, large single test doses have been used to derive the time of doubling survival ratio e.g. for epidermal clones. Although cryptogenic cell number per crypt can be virtually restored by day 4 after a single dose and probably after many such doses, the status quo cannot be reached until the number of crypts is restored to normal. Stem cell numbers form a necessary part of the integrity of epitheliums. The quality of the stem cell function of survivors as expressed in the differentiated progeny, and the maintenance of function of the supportive environment are equally important for late radiation damage. (Yamashita, S.)

  3. Stem cell sources for cardiac regeneration

    Roccio, M.; Goumans, M. J.; Sluijter, J. P. G.; Doevendans, P. A.

    Cell-based cardiac repair has the ambitious aim to replace the malfunctioning cardiac muscle developed after myocardial infarction, with new contractile cardiomyocytes and vessels. Different stem cell populations have been intensively studied in the last decade as a potential source of new

  4. Materializing Heart Regeneration: Biomimicry of Key Observations in Cell Transplantation Therapies and Natural Cardiac Regeneration

    Kong, Yen P.; Jongpaiboonkit, Leena

    2016-07-01

    New regenerative paradigms are needed to address the growing global problem of heart failure as existing interventions are unsatisfactory. Outcomes from the current paradigm of cell transplantation have not been stellar but the mechanistic knowledge learned from them is instructive in the development of future paradigms. An emerging biomaterial-based approach incorporating key mechanisms and additional ones scrutinized from the process of natural heart regeneration in zebrafish may become the next evolution in cardiac repair. We highlight, with examples, tested key concepts and pivotal ones that may be integrated into a successful therapy.

  5. Plasticity and regeneration in the injured spinal cord after cell transplantation therapy.

    Nori, Satoshi; Nakamura, Masaya; Okano, Hideyuki

    2017-01-01

    Spinal cord injury (SCI) typically damages the long axonal tracts of the spinal cord which results in permanent disability. However, regeneration of the injured spinal cord is approaching reality according to the advances in stem cell biology. Cell transplantation therapy holds potential to lead to recovery following SCI through some positive mechanisms. Grafted cells induce plasticity and regeneration in the injured spinal cord by promoting remyelination of damaged axons, reconstruction of neural circuits by synapse formation between host neurons and graft-derived neurons, and secreting neurotrophic factors to promote axonal elongation as well as reduce retrograde axonal degeneration. In this review, we will delineate (1) the microenvironment of the injured spinal cord that influence the plasticity and regeneration capacity after SCI, (2) a number of different kinds of cell transplantation therapies for SCI that has been extensively studied by researchers, and (3) potential mechanisms of grafted cell-induced regeneration and plasticity in the injured spinal cord. © 2017 Elsevier B.V. All rights reserved.

  6. Cell proliferation is necessary for the regeneration of oral structures in the anthozoan cnidarian Nematostella vectensis

    Passamaneck Yale J

    2012-12-01

    Full Text Available Abstract Background The contribution of cell proliferation to regeneration varies greatly between different metazoan models. Planarians rely on pluripotent neoblasts and amphibian limb regeneration depends upon formation of a proliferative blastema, while regeneration in Hydra can occur in the absence of cell proliferation. Recently, the cnidarian Nematostella vectensis has shown potential as a model for studies of regeneration because of the ability to conduct comparative studies of patterning during embryonic development, asexual reproduction, and regeneration. The present study investigates the pattern of cell proliferation during the regeneration of oral structures and the role of cell proliferation in this process. Results In intact polyps, cell proliferation is observed in both ectodermal and endodermal tissues throughout the entire oral-aboral axis, including in the tentacles and physa. Following bisection, there is initially little change in proliferation at the wound site of the aboral fragment, however, beginning 18 to 24 hours after amputation there is a dramatic increase in cell proliferation at the wound site in the aboral fragment. This elevated level of proliferation is maintained throughout the course or regeneration of oral structures, including the tentacles, the mouth, and the pharynx. Treatments with the cell proliferation inhibitors hydroxyurea and nocodazole demonstrate that cell proliferation is indispensable for the regeneration of oral structures. Although inhibition of regeneration by nocodazole was generally irreversible, secondary amputation reinitiates cell proliferation and regeneration. Conclusions The study has found that high levels of cell proliferation characterize the regeneration of oral structures in Nematostella, and that this cell proliferation is necessary for the proper progression of regeneration. Thus, while cell proliferation contributes to regeneration of oral structures in both Nematostella and

  7. Regeneration of tracheal epithelium using mouse induced pluripotent stem cells.

    Ikeda, Masakazu; Imaizumi, Mitsuyoshi; Yoshie, Susumu; Otsuki, Koshi; Miyake, Masao; Hazama, Akihiro; Wada, Ikuo; Omori, Koichi

    2016-01-01

    Conclusion The findings demonstrated the potential use of induced pluripotent stem cells for regeneration of tracheal epithelium. Objective Autologous tissue implantation techniques using skin or cartilage are often applied in cases of tracheal defects with laryngeal inflammatory lesions and malignant tumor invasion. However, these techniques are invasive with an unstable clinical outcome. The purpose of this study was to investigate regeneration in a tracheal defect site of nude rats after implantation of ciliated epithelium that was differentiated from induced pluripotent stem cells. Method Embryoid bodies were formed from mouse induced pluripotent stem cells. They were cultured with growth factors for 5 days, and then cultured at the air-liquid interface. The degree of differentiation achieved prior to implantation was determined by histological findings and the results of real-time polymerase chain reaction. Embryoid bodies including ciliated epithelium were embedded into collagen gel that served as an artificial scaffold, and then implanted into nude rats, creating an 'air-liquid interface model'. Histological evaluation was performed 7 days after implantation. Results The ciliated epithelial structure survived on the lumen side of regenerated tissue. It was demonstrated histologically that the structure was composed of ciliated epithelial cells.

  8. Retinal stem cells and regeneration of vision system.

    Yip, Henry K

    2014-01-01

    The vertebrate retina is a well-characterized model for studying neurogenesis. Retinal neurons and glia are generated in a conserved order from a pool of mutlipotent progenitor cells. During retinal development, retinal stem/progenitor cells (RPC) change their competency over time under the influence of intrinsic (such as transcriptional factors) and extrinsic factors (such as growth factors). In this review, we summarize the roles of these factors, together with the understanding of the signaling pathways that regulate eye development. The information about the interactions between intrinsic and extrinsic factors for retinal cell fate specification is useful to regenerate specific retinal neurons from RPCs. Recent studies have identified RPCs in the retina, which may have important implications in health and disease. Despite the recent advances in stem cell biology, our understanding of many aspects of RPCs in the eye remains limited. PRCs are present in the developing eye of all vertebrates and remain active in lower vertebrates throughout life. In mammals, however, PRCs are quiescent and exhibit very little activity and thus have low capacity for retinal regeneration. A number of different cellular sources of RPCs have been identified in the vertebrate retina. These include PRCs at the retinal margin, pigmented cells in the ciliary body, iris, and retinal pigment epithelium, and Müller cells within the retina. Because PRCs can be isolated and expanded from immature and mature eyes, it is possible now to study these cells in culture and after transplantation in the degenerated retinal tissue. We also examine current knowledge of intrinsic RPCs, and human embryonic stems and induced pluripotent stem cells as potential sources for cell transplant therapy to regenerate the diseased retina. Copyright © 2013 Wiley Periodicals, Inc.

  9. Stem cell  mediated liver regeneration:

    Jelnes, Peter

    udformet en strategi som involverede isolering af HPCr vha. Fluorescent Activated Cell Sorting (FACS). Isolerede celler skulle efterfølgende undersøges ved in vitro studier som implicerede tilsætning af specifikke immunrespons relaterede faktorer. Kun få specifikke overflade HPC markører er blevet...

  10. MicroRNA profiling of antler stem cells in potentiated and dormant states and their potential roles in antler regeneration.

    Ba, Hengxing; Wang, Datao; Li, Chunyi

    2016-04-01

    MicroRNAs (miRNAs) can effectively regulate gene expression at the post-transcriptional level and play a critical role in tissue growth, development and regeneration. Our previous studies showed that antler regeneration is a stem cell-based process and antler stem cells reside in the periosteum of a pedicle, the permanent bony protuberance, from which antler regeneration takes place. Antlers are the only mammalian organ that can fully regenerate and hence provide a unique opportunity to identify miRNAs that are involved in organ regeneration. In the present study, we used next generation sequencing technology sequenced miRNAs of the stem cells derived from either the potentiated or the dormant pedicle periosteum. A population of both conserved and 20 deer-specific miRNAs was identified. These conserved miRNAs were derived from 453 homologous hairpin precursors across 88 animal species, and were further grouped into 167 miRNA families. Among them, the miR-296 is embryonic stem cell-specific. The potentiation process resulted in the significant regulation (>±2 Fold, q value cell potentiation process. This research has identified miRNAs that are associated either with the dormant or the potentiated antler stem cells and identified some target miRNAs for further research into their role played in mammalian organ regeneration.

  11. Mesenchymal Stem Cells for Cartilage Regeneration of TMJ Osteoarthritis

    Dixin Cui

    2017-01-01

    Full Text Available Temporomandibular joint osteoarthritis (TMJ OA is a degenerative disease, characterized by progressive cartilage degradation, subchondral bone remodeling, synovitis, and chronic pain. Due to the limited self-healing capacity in condylar cartilage, traditional clinical treatments have limited symptom-modifying and structure-modifying effects to restore impaired cartilage as well as other TMJ tissues. In recent years, stem cell-based therapy has raised much attention as an alternative approach towards tissue repair and regeneration. Mesenchymal stem cells (MSCs, derived from the bone marrow, synovium, and even umbilical cord, play a role as seed cells for the cartilage regeneration of TMJ OA. MSCs possess multilineage differentiation potential, including chondrogenic differentiation as well as osteogenic differentiation. In addition, the trophic modulations of MSCs exert anti-inflammatory and immunomodulatory effects under aberrant conditions. Furthermore, MSCs combined with appropriate scaffolds can form cartilaginous or even osseous compartments to repair damaged tissue and impaired function of TMJ. In this review, we will briefly discuss the pathogenesis of cartilage degeneration in TMJ OA and emphasize the potential sources of MSCs and novel approaches for the cartilage regeneration of TMJ OA, particularly focusing on the MSC-based therapy and tissue engineering.

  12. Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration.

    Lee, Sang Goo; Huang, Mingqian; Obholzer, Nikolaus D; Sun, Shan; Li, Wenyan; Petrillo, Marco; Dai, Pu; Zhou, Yi; Cotanche, Douglas A; Megason, Sean G; Li, Huawei; Chen, Zheng-Yi

    2016-01-01

    Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration.

  13. Stem Cell Extracellular Vesicles: Extended Messages of Regeneration

    Riazifar, Milad; Pone, Egest J.; Lötvall, Jan; Zhao, Weian

    2017-01-01

    Stem cells are critical to maintaining steady-state organ homeostasis and regenerating injured tissues. Recent intriguing reports implicate extracellular vesicles (EVs) as carriers for the distribution of morphogens and growth and differentiation factors from tissue parenchymal cells to stem cells, and conversely, stem cell–derived EVs carrying certain proteins and nucleic acids can support healing of injured tissues. We describe approaches to make use of engineered EVs as technology platforms in therapeutics and diagnostics in the context of stem cells. For some regenerative therapies, natural and engineered EVs from stem cells may be superior to single-molecule drugs, biologics, whole cells, and synthetic liposome or nanoparticle formulations because of the ease of bioengineering with multiple factors while retaining superior biocompatibility and biostability and posing fewer risks for abnormal differentiation or neoplastic transformation. Finally, we provide an overview of current challenges and future directions of EVs as potential therapeutic alternatives to cells for clinical applications. PMID:27814025

  14. The cell cycle as a brake for β-cell regeneration from embryonic stem cells.

    El-Badawy, Ahmed; El-Badri, Nagwa

    2016-01-13

    The generation of insulin-producing β cells from stem cells in vitro provides a promising source of cells for cell transplantation therapy in diabetes. However, insulin-producing cells generated from human stem cells show deficiency in many functional characteristics compared with pancreatic β cells. Recent reports have shown molecular ties between the cell cycle and the differentiation mechanism of embryonic stem (ES) cells, assuming that cell fate decisions are controlled by the cell cycle machinery. Both β cells and ES cells possess unique cell cycle machinery yet with significant contrasts. In this review, we compare the cell cycle control mechanisms in both ES cells and β cells, and highlight the fundamental differences between pluripotent cells of embryonic origin and differentiated β cells. Through critical analysis of the differences of the cell cycle between these two cell types, we propose that the cell cycle of ES cells may act as a brake for β-cell regeneration. Based on these differences, we discuss the potential of modulating the cell cycle of ES cells for the large-scale generation of functionally mature β cells in vitro. Further understanding of the factors that modulate the ES cell cycle will lead to new approaches to enhance the production of functional mature insulin-producing cells, and yield a reliable system to generate bona fide β cells in vitro.

  15. The regeneration of epidermal cells of Saintpaulia leaves as a new plant-tissue system for cellular radiation biology

    Engels, F.M.; Laan, F.M. van der; Leenhouts, H.P.; Chadwick, K.H.

    1980-01-01

    investigation of the nucleus of epidermal cells of the petioles of Saintpaulia leaves by cytofluorimetry revealed that all cells are in a non-cycling pre DNA synthesis phase. Cultivation of dissected leaves results in a synchronous regeneration process of a defined number of cells. Five days after onset of cultivation the cells reach the first mitosis. The nuclear development during the regeneration process is described. Irradiation of the leaves results in a directly visible inhibition of this regenerating capability which is used to quantify cell survival in a tissue. The data show that the radiation response has a similar shape to that of the survival of single cells in culture. This response can be observed before the first mitosis of the cells and its application as a new plant tissue system for cellular radiation research is discussed. (author)

  16. Biomaterial property-controlled stem cell fates for cardiac regeneration

    Yanyi Xu

    2016-09-01

    Full Text Available Myocardial infarction (MI affects more than 8 million people in the United States alone. Due to the insufficient regeneration capacity of the native myocardium, one widely studied approach is cardiac tissue engineering, in which cells are delivered with or without biomaterials and/or regulatory factors to fully regenerate the cardiac functions. Specifically, in vitro cardiac tissue engineering focuses on using biomaterials as a reservoir for cells to attach, as well as a carrier of various regulatory factors such as growth factors and peptides, providing high cell retention and a proper microenvironment for cells to migrate, grow and differentiate within the scaffolds before implantation. Many studies have shown that the full establishment of a functional cardiac tissue in vitro requires synergistic actions between the seeded cells, the tissue culture condition, and the biochemical and biophysical environment provided by the biomaterials-based scaffolds. Proper electrical stimulation and mechanical stretch during the in vitro culture can induce the ordered orientation and differentiation of the seeded cells. On the other hand, the various scaffolds biochemical and biophysical properties such as polymer composition, ligand concentration, biodegradability, scaffold topography and mechanical properties can also have a significant effect on the cellular processes.

  17. Application of Novel Drugs for Corneal Cell Regeneration

    Sang Beom Han

    2018-01-01

    Full Text Available Corneal transplantation has been the only treatment method for corneal blindness, which is the major cause of reversible blindness. However, despite the advancement of surgical techniques for corneal transplantation, demand for the surgery can never be met due to a global shortage of donor cornea. The development of bioengineering and pharmaceutical technology provided us with novel drugs and biomaterials that can be used for innovative treatment methods for corneal diseases. In this review, the authors will discuss the efficacy and safety of pharmacologic therapies, such as Rho-kinase (ROCK inhibitors, blood-derived products, growth factors, and regenerating agent on corneal cell regeneration. The promising results of these agents suggest that these can be viable options for corneal reconstruction and visual rehabilitation.

  18. Dental Pulp Stem Cells as a multifaceted tool for bioengineering and the regeneration of craniomaxillofacial tissues

    Maitane eAurrekoetxea

    2015-10-01

    Full Text Available Dental pulp stem cells, or DPSC, are neural crest-derived cells with an outstanding capacity to differentiate along multiple cell lineages of interest for cell therapy. In particular, highly efficient osteo/dentinogenic differentiation of DPSC can be achieved using simple in vitro protocols, making these cells a very attractive and promising tool for the future treatment of dental and periodontal diseases. Among craniomaxillofacial organs, the tooth and salivary gland are two such cases in which complete regeneration by tissue engineering using DPSC appears to be possible, as research over the last decade has made substantial progress in experimental models of partial or total regeneration of both organs, by cell recombination technology. Moreover, DPSC seem to be a particularly good choice for the regeneration of nerve tissues, including injured or transected cranial nerves. In this context, the oral cavity appears to be an excellent testing ground for new regenerative therapies using DPSC. However, many issues and challenges need yet to be addressed before these cells can be employed in clinical therapy. In this review, we point out some important aspects on the biology of DPSC with regard to their use for the reconstruction of different craniomaxillofacial tissues and organs, with special emphasis on cranial bones, nerves, teeth, and salivary glands. We suggest new ideas and strategies to fully exploit the capacities of DPSC for bioengineering of the aforementioned tissues.

  19. Can stem cells really regenerate the human heart? Use your noggin, dickkopf! Lessons from developmental biology.

    Sommer, Paula

    2013-06-01

    The human heart is the first organ to develop and its development is fairly well characterised. In theory, the heart has the capacity to regenerate, as its cardiomyocytes may be capable of cell division and the adult heart contains a cardiac stem cell niche, presumably capable of differentiating into cardiomyocytes and other cardiac-associated cell types. However, as with most other organs, these mechanisms are not activated upon serious injury. Several experimental options to induce regeneration of the damaged heart tissue are available: activate the endogenous cardiomyocytes to divide, coax the endogenous population of stem cells to divide and differentiate, or add exogenous cell-based therapy to replace the lost cardiac tissue. This review is a summary of the recent research into all these avenues, discussing the reasons for the limited successes of clinical trials using stem cells after cardiac injury and explaining new advances in basic science. It concludes with a reiteration that chances of successful regeneration would be improved by understanding and implementing the basics of heart development and stem cell biology.

  20. Augmentation of musculoskeletal regeneration: role for pluripotent stem cells.

    Jevons, Lauren A; Houghton, Franchesca D; Tare, Rahul S

    2018-03-20

    The rise in the incidence of musculoskeletal diseases is attributed to an increasing ageing population. The debilitating effects of musculoskeletal diseases, coupled with a lack of effective therapies, contribute to huge financial strains on healthcare systems. The focus of regenerative medicine has shifted to pluripotent stem cells (PSCs), namely, human embryonic stem cells and human-induced PSCs, due to the limited success of adult stem cell-based interventions. PSCs constitute a valuable cell source for musculoskeletal regeneration due to their capacity for unlimited self-renewal, ability to differentiate into all cell lineages of the three germ layers and perceived immunoprivileged characteristics. This review summarizes methods for chondrogenic, osteogenic, myogenic and adipogenic differentiation of PSCs and their potential for therapeutic applications.

  1. Regenerating reptile retinas: a comparative approach to restoring retinal ganglion cell function.

    Williams, D L

    2017-02-01

    Transection or damage to the mammalian optic nerve generally results in loss of retinal ganglion cells by apoptosis. This cell death is seen less in fish or amphibians where retinal ganglion cell survival and axon regeneration leads to recovery of sight. Reptiles lie somewhere in the middle of this spectrum of nerve regeneration, and different species have been reported to have a significant variation in their retinal ganglion cell regenerative capacity. The ornate dragon lizard Ctenophoris ornatus exhibits a profound capacity for regeneration, whereas the Tenerife wall lizard Gallotia galloti has a more variable response to optic nerve damage. Some individuals regain visual activity such as the pupillomotor responses, whereas in others axons fail to regenerate sufficiently. Even in Ctenophoris, although the retinal ganglion cell axons regenerate adequately enough to synapse in the tectum, they do not make long-term topographic connections allowing recovery of complex visually motivated behaviour. The question then centres on where these intraspecies differences originate. Is it variation in the innate ability of retinal ganglion cells from different species to regenerate with functional validity? Or is it variances between different species in the substrate within which the nerves regenerate, the extracellular environment of the damaged nerve or the supporting cells surrounding the regenerating axons? Investigations of retinal ganglion cell regeneration between different species of lower vertebrates in vivo may shed light on these questions. Or perhaps more interesting are in vitro studies comparing axon regeneration of retinal ganglion cells from various species placed on differing substrates.

  2. Influence of nanotopography on periodontal ligament stem cell functions and cell sheet based periodontal regeneration.

    Gao, Hui; Li, Bei; Zhao, Lingzhou; Jin, Yan

    2015-01-01

    Periodontal regeneration is an important part of regenerative medicine, with great clinical significance; however, the effects of nanotopography on the functions of periodontal ligament (PDL) stem cells (PDLSCs) and on PDLSC sheet based periodontal regeneration have never been explored. Titania nanotubes (NTs) layered on titanium (Ti) provide a good platform to study this. In the current study, the influence of NTs of different tube size on the functions of PDLSCs was observed. Afterward, an ectopic implantation model using a Ti/cell sheets/hydroxyapatite (HA) complex was applied to study the effect of the NTs on cell sheet based periodontal regeneration. The NTs were able to enhance the initial PDLSC adhesion and spread, as well as collagen secretion. With the Ti/cell sheets/HA complex model, it was demonstrated that the PDLSC sheets were capable of regenerating the PDL tissue, when combined with bone marrow mesenchymal stem cell (BMSC) sheets and HA, without the need for extra soluble chemical cues. Simultaneously, the NTs improved the periodontal regeneration result of the ectopically implanted Ti/cell sheets/HA complex, giving rise to functionally aligned collagen fiber bundles. Specifically, much denser collagen fibers, with abundant blood vessels as well as cementum-like tissue on the Ti surface, which well-resembled the structure of natural PDL, were observed in the NT5 and NT10 sample groups. Our study provides the first evidence that the nanotopographical cues obviously influence the functions of PDLSCs and improve the PDLSC sheet based periodontal regeneration size dependently, which provides new insight to the periodontal regeneration. The Ti/cell sheets/HA complex may constitute a good model to predict the effect of biomaterials on periodontal regeneration.

  3. Transplantation of autologous synovial mesenchymal stem cells promotes meniscus regeneration in aged primates.

    Kondo, Shimpei; Muneta, Takeshi; Nakagawa, Yusuke; Koga, Hideyuki; Watanabe, Toshifumi; Tsuji, Kunikazu; Sotome, Shinichi; Okawa, Atsushi; Kiuchi, Shinji; Ono, Hideo; Mizuno, Mitsuru; Sekiya, Ichiro

    2017-06-01

    Transplantation of aggregates of synovial mesenchymal stem cells (MSCs) enhanced meniscus regeneration in rats. Anatomy and biological properties of the meniscus depend on animal species. To apply this technique clinically, it is valuable to investigate the use of animals genetically close to humans. We investigated whether transplantation of aggregates of autologous synovial MSCs promoted meniscal regeneration in aged primates. Chynomolgus primates between 12 and 13 years old were used. After the anterior halves of the medial menisci in both knees were removed, an average of 14 aggregates consisting of 250,000 synovial MSCs were transplanted onto the meniscus defect. No aggregates were transplanted to the opposite knee for the control. Meniscus and articular cartilage were analyzed macroscopically, histologically, and by MRI T1rho mapping at 8 (n = 3) and 16 weeks (n = 4). The medial meniscus was larger and the modified Pauli's histological score for the regenerated meniscus was better in the MSC group than in the control group in each primate at 8 and 16 weeks. Mankin's score for the medial femoral condyle cartilage was better in the MSC group than in the control group in all primates at 16 weeks. T1rho value for both the regenerated meniscus and adjacent articular cartilage in the MSC group was closer to the normal meniscus than in the control group in all primates at 16 weeks. Transplantation of aggregates of autologous synovial MSCs promoted meniscus regeneration and delayed progression of degeneration of articular cartilage in aged primates. This is the first report dealing with meniscus regeneration in primates. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1274-1282, 2017. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  4. Impact of cycling cells and cell cycle regulation on Hydra regeneration.

    Buzgariu, Wanda; Wenger, Yvan; Tcaciuc, Nina; Catunda-Lemos, Ana-Paula; Galliot, Brigitte

    2018-01-15

    Hydra tissues are made from three distinct populations of stem cells that continuously cycle and pause in G2 instead of G1. To characterize the role of cell proliferation after mid-gastric bisection, we have (i) used flow cytometry and classical markers to monitor cell cycle modulations, (ii) quantified the transcriptomic regulations of 202 genes associated with cell proliferation during head and foot regeneration, and (iii) compared the impact of anti-proliferative treatments on regeneration efficiency. We confirm two previously reported events: an early mitotic wave in head-regenerating tips, when few cell cycle genes are up-regulated, and an early-late wave of proliferation on the second day, preceded by the up-regulation of 17 cell cycle genes. These regulations appear more intense after mid-gastric bisection than after decapitation, suggesting a position-dependent regulation of cell proliferation during head regeneration. Hydroxyurea, which blocks S-phase progression, delays head regeneration when applied before but not after bisection. This result is consistent with the fact that the Hydra central region is enriched in G2-paused adult stem cells, poised to divide upon injury, thus forming a necessary constitutive pro-blastema. However a prolonged exposure to hydroxyurea does not block regeneration as cells can differentiate apical structures without traversing S-phase, and also escape in few days the hydroxyurea-induced S-phase blockade. Thus Hydra head regeneration, which is a fast event, is highly plastic, relying on large stocks of adult stem cells paused in G2 at amputation time, which immediately divide to proliferate and/or differentiate apical structures even when S-phase is blocked. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Bottlenecks in the generation and maintenance of morphogenic banana cell suspensions and plant regeneration via somatic embryogenesis therefrom

    Schoofs, H.; Panis, B.; Strosse, H.; Mosqueda, A. M.; Torres, J. L.; Roux, N.; Doležel, Jaroslav; Swennen, R.

    2001-01-01

    Roč. 8, č. 2 (2001), s. 3-7 ISSN 0989-8972 R&D Projects: GA MŠk ME 376 Institutional research plan: CEZ:AV0Z5038910 Keywords : banana cell suspensions * plant regeneration Subject RIV: EA - Cell Biology

  6. MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration

    Mokalled, Mayssa H.; Johnson, Aaron N.; Creemers, Esther E.; Olson, Eric N.

    2012-01-01

    Muscle repair is regulated by satellite cells, adult skeletal muscle stem cells that control muscle regeneration by proliferating and fusing with injured myofibers. MyoD is required for muscle regeneration; however, the mechanisms regulating MyoD expression in satellite cells are unclear. In this study, Olson and colleagues have demonstrated that deletion of MASTR and MRTF-A, two members of the Myocardin family of transcription factors, leads to skeletal muscle regeneration defects and down-r...

  7. Workshop on programming beta cell development, impairment and regeneration

    Heller, Scott; Nielsen, Jens Høiriis

    2012-01-01

    Helsingør, the city of Hamlet in Denmark, provided the site for the workshop "Programming Beta Cell Development, Impairment and Regeneration" on October 23-26th, 2011. The same location has held two EASD Islet study group meetings, while the previous three workshops were held in Helsinki, Finland...... (2003), El Perello, Spain (2006) and Peebles, Scotland (2009). The meeting drew 190 attendees from 12 different countries. There were 37 main oral presentations, and 68 posters covered virtually all aspects of the pancreas and provided a dynamic snapshot of the most interesting areas of current...

  8. Bioprinting for stem cell research

    Tasoglu, Savas; Demirci, Utkan

    2012-01-01

    Recently, there has been a growing interest to apply bioprinting techniques to stem cell research. Several bioprinting methods have been developed utilizing acoustics, piezoelectricity, and lasers to deposit living cells onto receiving substrates. Using these technologies, spatially defined gradients of immobilized proteins can be engineered to direct stem cell differentiation into multiple subpopulations of different lineages. Stem cells can also be patterned in a high-throughput manner onto flexible implementation patches for tissue regeneration or onto substrates with the goal of accessing encapsulated stem cell of interest for genomic analysis. Here, we review recent achievements with bioprinting technologies in stem cell research, and identify future challenges and potential applications including tissue engineering and regenerative medicine, wound healing, and genomics. PMID:23260439

  9. Localization and characterization of STRO-1 cells in the deer pedicle and regenerating antler.

    Hans J Rolf

    2008-04-01

    Full Text Available The annual regeneration of deer antlers is a unique developmental event in mammals, which as a rule possess only a very limited capacity to regenerate lost appendages. Studying antler regeneration can therefore provide a deeper insight into the mechanisms that prevent limb regeneration in humans and other mammals, and, with regard to medical treatments, may possibly even show ways how to overcome these limitations. Traditionally, antler regeneration has been characterized as a process involving the formation of a blastema from de-differentiated cells. More recently it has, however, been hypothesized that antler regeneration is a stem cell-based process. Thus far, direct evidence for the presence of stem cells in primary or regenerating antlers was lacking. Here we demonstrate the presence of cells positive for the mesenchymal stem cell marker STRO-1 in the chondrogenic growth zone and the perivascular tissue of the cartilaginous zone in primary and regenerating antlers as well as in the pedicle of fallow deer (Dama dama. In addition, cells positive for the stem cell/progenitor cell markers STRO-1, CD133 and CD271 (LNGFR were isolated from the growth zones of regenerating fallow deer antlers as well as the pedicle periosteum and cultivated for extended periods of time. We found evidence that STRO-1(+ cells isolated from the different locations are able to differentiate in vitro along the osteogenic and adipogenic lineages. Our results support the view that the annual process of antler regeneration might depend on the periodic activation of mesenchymal progenitor cells located in the pedicle periosteum. The findings of the present study indicate that not only limited tissue regeneration, but also extensive appendage regeneration in a postnatal mammal can occur as a stem cell-based process.

  10. Stem cell research: applicability in dentistry.

    Mathur, Shivani; Chopra, Rahul; Pandit, I K; Srivastava, Nikhil; Gugnani, Neeraj

    2014-01-01

    In the face of extraordinary advances in the prevention, diagnosis, and treatment of human diseases, the inability of most tissues and organs to repair and regenerate after damage is a problem that needs to be solved. Stem cell research is being pursued in the hope of achieving major medical breakthroughs. Scientists are striving to create therapies that rebuild or replace damaged cells with tissues grown from stem cells that will offer hope to people suffering from various ailments. Regeneration of damaged periodontal tissue, bone, pulp, and dentin is a problem that dentists face today. Stem cells present in dental pulp, periodontal ligament, and alveolar bone marrow have the potential to repair and regenerate teeth and periodontal structures. These stem cells can be harvested from dental pulp, periodontal ligament, and/or alveolar bone marrow; expanded; embedded in an appropriate scaffold; and transplanted back into a defect to regenerate bone and tooth structures. These cells have the potential to regenerate dentin, periodontal ligament, and cementum and can also be used to restore bone defects. The kind of scaffold, the source of cells, the type of in vitro culturing, and the type of surgical procedure to be used all require careful consideration. The endeavor is clearly multidisciplinary in nature, and the practicing dental surgeon has a critical role in it. Playing this role in the most effective way requires awareness of the huge potential associated with the use of stem cells in a clinical setting, as well as a proper understanding of the related problems.

  11. Research Note Effects of previous cultivation on regeneration of ...

    We investigated the effects of previous cultivation on regeneration potential under miombo woodlands in a resettlement area, a spatial product of Zimbabwe's land reforms. We predicted that cultivation would affect population structure, regeneration, recruitment and potential grazing capacity of rangelands. Plant attributes ...

  12. Translational findings from cardiovascular stem cell research.

    Mazhari, Ramesh; Hare, Joshua M

    2012-01-01

    The possibility of using stem cells to regenerate damaged myocardium has been actively investigated since the late 1990s. Consistent with the traditional view that the heart is a "postmitotic" organ that possesses minimal capacity for self-repair, much of the preclinical and clinical work has focused exclusively on introducing stem cells into the heart, with the hope of differentiation of these cells into functioning cardiomyocytes. This approach is ongoing and retains promise but to date has yielded inconsistent successes. More recently, it has become widely appreciated that the heart possesses endogenous repair mechanisms that, if adequately stimulated, might regenerate damaged cardiac tissue from in situ cardiac stem cells. Accordingly, much recent work has focused on engaging and enhancing endogenous cardiac repair mechanisms. This article reviews the literature on stem cell-based myocardial regeneration, placing emphasis on the mutually enriching interaction between basic and clinical research. Copyright © 2012 Elsevier Inc. All rights reserved.

  13. Cell lineage identification and stem cell culture in a porcine model for the study of intestinal epithelial regeneration.

    Liara M Gonzalez

    Full Text Available Significant advances in intestinal stem cell biology have been made in murine models; however, anatomical and physiological differences between mice and humans limit mice as a translational model for stem cell based research. The pig has been an effective translational model, and represents a candidate species to study intestinal epithelial stem cell (IESC driven regeneration. The lack of validated reagents and epithelial culture methods is an obstacle to investigating IESC driven regeneration in a pig model. In this study, antibodies against Epithelial Adhesion Molecule 1 (EpCAM and Villin marked cells of epithelial origin. Antibodies against Proliferative Cell Nuclear Antigen (PCNA, Minichromosome Maintenance Complex 2 (MCM2, Bromodeoxyuridine (BrdU and phosphorylated Histone H3 (pH3 distinguished proliferating cells at various stages of the cell cycle. SOX9, localized to the stem/progenitor cells zone, while HOPX was restricted to the +4/'reserve' stem cell zone. Immunostaining also identified major differentiated lineages. Goblet cells were identified by Mucin 2 (MUC2; enteroendocrine cells by Chromogranin A (CGA, Gastrin and Somatostatin; and absorptive enterocytes by carbonic anhydrase II (CAII and sucrase isomaltase (SIM. Transmission electron microscopy demonstrated morphologic and sub-cellular characteristics of stem cell and differentiated intestinal epithelial cell types. Quantitative PCR gene expression analysis enabled identification of stem/progenitor cells, post mitotic cell lineages, and important growth and differentiation pathways. Additionally, a method for long-term culture of porcine crypts was developed. Biomarker characterization and development of IESC culture in the porcine model represents a foundation for translational studies of IESC-driven regeneration of the intestinal epithelium in physiology and disease.

  14. Mesenchymal Stem Cells of Dental Origin for Inducing Tissue Regeneration in Periodontitis: A Mini-Review

    Beatriz Hernández-Monjaraz

    2018-03-01

    Full Text Available Periodontitis is a chronic disease that begins with a period of inflammation of the supporting tissues of the teeth table and then progresses, destroying the tissues until loss of the teeth occurs. The restoration of the damaged dental support apparatus is an extremely complex process due to the regeneration of the cementum, the periodontal ligament, and the alveolar bone. Conventional treatment relies on synthetic materials that fill defects and replace lost dental tissue, but these approaches are not substitutes for a real regeneration of tissue. To address this, there are several approaches to tissue engineering for regenerative dentistry, among them, the use of stem cells. Mesenchymal stem cells (MSC can be obtained from various sources of adult tissues, such as bone marrow, adipose tissue, skin, and tissues of the orofacial area. MSC of dental origin, such as those found in the bone marrow, have immunosuppressive and immunotolerant properties, multipotency, high proliferation rates, and the capacity for tissue repair. However, they are poorly used as sources of tissue for therapeutic purposes. Their accessibility makes them an attractive source of mesenchymal stem cells, so this review describes the field of dental stem cell research and proposes a potential mechanism involved in periodontal tissue regeneration induced by dental MSC.

  15. Stable subcutaneous cartilage regeneration of bone marrow stromal cells directed by chondrocyte sheet.

    Li, Dan; Zhu, Lian; Liu, Yu; Yin, Zongqi; Liu, Yi; Liu, Fangjun; He, Aijuan; Feng, Shaoqing; Zhang, Yixin; Zhang, Zhiyong; Zhang, Wenjie; Liu, Wei; Cao, Yilin; Zhou, Guangdong

    2017-05-01

    In vivo niche plays an important role in regulating differentiation fate of stem cells. Due to lack of proper chondrogenic niche, stable cartilage regeneration of bone marrow stromal cells (BMSCs) in subcutaneous environments is always a great challenge. This study explored the feasibility that chondrocyte sheet created chondrogenic niche retained chondrogenic phenotype of BMSC engineered cartilage (BEC) in subcutaneous environments. Porcine BMSCs were seeded into biodegradable scaffolds followed by 4weeks of chondrogenic induction in vitro to form BEC, which were wrapped with chondrocyte sheets (Sheet group), acellular small intestinal submucosa (SIS, SIS group), or nothing (Blank group) respectively and then implanted subcutaneously into nude mice to trace the maintenance of chondrogenic phenotype. The results showed that all the constructs in Sheet group displayed typical cartilaginous features with abundant lacunae and cartilage specific matrices deposition. These samples became more mature with prolonged in vivo implantation, and few signs of ossification were observed at all time points except for one sample that had not been wrapped completely. Cell labeling results in Sheet group further revealed that the implanted BEC directly participated in cartilage formation. Samples in both SIS and Blank groups mainly showed ossified tissue at all time points with partial fibrogenesis in a few samples. These results suggested that chondrocyte sheet could create a chondrogenic niche for retaining chondrogenic phenotype of BEC in subcutaneous environment and thus provide a novel research model for stable ectopic cartilage regeneration based on stem cells. In vivo niche plays an important role in directing differentiation fate of stem cells. Due to lack of proper chondrogenic niche, stable cartilage regeneration of bone marrow stromal cells (BMSCs) in subcutaneous environments is always a great challenge. The current study demonstrated that chondrocyte sheet generated by

  16. Eye Absence Does Not Regulate Planarian Stem Cells during Eye Regeneration.

    LoCascio, Samuel A; Lapan, Sylvain W; Reddien, Peter W

    2017-02-27

    Dividing cells called neoblasts contain pluripotent stem cells and drive planarian flatworm regeneration from diverse injuries. A long-standing question is whether neoblasts directly sense and respond to the identity of missing tissues during regeneration. We used the eye to investigate this question. Surprisingly, eye removal was neither sufficient nor necessary for neoblasts to increase eye progenitor production. Neoblasts normally increase eye progenitor production following decapitation, facilitating regeneration. Eye removal alone, however, did not induce this response. Eye regeneration following eye-specific resection resulted from homeostatic rates of eye progenitor production and less cell death in the regenerating eye. Conversely, large head injuries that left eyes intact increased eye progenitor production. Large injuries also non-specifically increased progenitor production for multiple uninjured tissues. We propose a model for eye regeneration in which eye tissue production by planarian stem cells is not directly regulated by the absence of the eye itself. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Distinct roles of neuroepithelial-like and radial glia-like progenitor cells in cerebellar regeneration.

    Kaslin, Jan; Kroehne, Volker; Ganz, Julia; Hans, Stefan; Brand, Michael

    2017-04-15

    Zebrafish can regenerate after brain injury, and the regenerative process is driven by resident stem cells. Stem cells are heterogeneous in the vertebrate brain, but the significance of having heterogeneous stem cells in regeneration is not understood. Limited availability of specific stem cells might impair the regeneration of particular cell lineages. We studied regeneration of the adult zebrafish cerebellum, which contains two major stem and progenitor cell types: ventricular zone and neuroepithelial cells. Using conditional lineage tracing we demonstrate that cerebellar regeneration depends on the availability of specific stem cells. Radial glia-like cells are thought to be the predominant stem cell type in homeostasis and after injury. However, we find that radial glia-like cells play a minor role in adult cerebellar neurogenesis and in recovery after injury. Instead, we find that neuroepithelial cells are the predominant stem cell type supporting cerebellar regeneration after injury. Zebrafish are able to regenerate many, but not all, cell types in the cerebellum, which emphasizes the need to understand the contribution of different adult neural stem and progenitor cell subtypes in the vertebrate central nervous system. © 2017. Published by The Company of Biologists Ltd.

  18. Diphtheria Toxin-Induced Cell Death Triggers Wnt-Dependent Hair Cell Regeneration in Neonatal Mice.

    Hu, Lingxiang; Lu, Jingrong; Chiang, Hao; Wu, Hao; Edge, Albert S B; Shi, Fuxin

    2016-09-07

    Cochlear hair cells (HCs), the sensory cells that respond to sound, do not regenerate after damage in adult mammals, and their loss is a major cause of deafness. Here we show that HC regeneration in newborn mouse ears occurred spontaneously when the original cells were ablated by treatment with diphtheria toxin (DT) in ears that had been engineered to overexpress the DT receptor, but was not detectable when HCs were ablated in vivo by the aminoglycoside antibiotic neomycin. A variety of Wnts (Wnt1, Wnt2, Wnt2b, Wnt4, Wnt5a, Wnt7b, Wnt9a, Wnt9b, and Wnt11) and Wnt pathway component Krm2 were upregulated after DT damage. Nuclear β-catenin was upregulated in HCs and supporting cells of the DT-damaged cochlea. Pharmacological inhibition of Wnt decreased spontaneous regeneration, confirming a role of Wnt signaling in HC regeneration. Inhibition of Notch signaling further potentiated supporting cell proliferation and HC differentiation that occurred spontaneously. The absence of new HCs in the neomycin ears was correlated to less robust Wnt pathway activation, but the ears subjected to neomycin treatment nonetheless showed increased cell division and HC differentiation after subsequent forced upregulation of β-catenin. These studies suggest, first, that Wnt signaling plays a key role in regeneration, and, second, that the outcome of a regenerative response to damage in the newborn cochlea is determined by reaching a threshold level of Wnt signaling rather than its complete absence or presence. Sensory HCs of the inner ear do not regenerate in the adult, and their loss is a major cause of deafness. We found that HCs regenerated spontaneously in the newborn mouse after diphtheria toxin (DT)-induced, but not neomycin-induced, HC death. Regeneration depended on activation of Wnt signaling, and regeneration in DT-treated ears correlated to a higher level of Wnt activation than occurred in nonregenerating neomycin-treated ears. This is significant because insufficient

  19. Feathers and fins: non-mammalian models for hair cell regeneration.

    Brignull, Heather R; Raible, David W; Stone, Jennifer S

    2009-06-24

    Death of mechanosensory cells in the inner ear results in two profound disabilities: hearing loss and balance disorders. Although mammals lack the capacity to regenerate hair cells, recent studies in mice and other rodents have offered valuable insight into strategies for stimulating hair cell regeneration in mammals. Investigations of model organisms that retain the ability to form new hair cells after embryogenesis, such as fish and birds, are equally important and have provided clues as to the cellular and molecular mechanisms that may block hair cell regeneration in mammals. Here, we summarize studies on hair cell regeneration in the chicken and the zebrafish, discuss specific advantages of each model, and propose future directions for the use of non-mammalian models in understanding hair cell regeneration.

  20. Lsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells.

    Tosic, Milica; Allen, Anita; Willmann, Dominica; Lepper, Christoph; Kim, Johnny; Duteil, Delphine; Schüle, Roland

    2018-01-25

    Satellite cells are muscle stem cells required for muscle regeneration upon damage. Of note, satellite cells are bipotent and have the capacity to differentiate not only into skeletal myocytes, but also into brown adipocytes. Epigenetic mechanisms regulating fate decision and differentiation of satellite cells during muscle regeneration are not yet fully understood. Here, we show that elevated levels of lysine-specific demethylase 1 (Kdm1a, also known as Lsd1) have a beneficial effect on muscle regeneration and recovery after injury, since Lsd1 directly regulates key myogenic transcription factor genes. Importantly, selective Lsd1 ablation or inhibition in Pax7-positive satellite cells, not only delays muscle regeneration, but changes cell fate towards brown adipocytes. Lsd1 prevents brown adipocyte differentiation of satellite cells by repressing expression of the novel pro-adipogenic transcription factor Glis1. Together, downregulation of Glis1 and upregulation of the muscle-specific transcription program ensure physiological muscle regeneration.

  1. Synovium-derived stem cells: a tissue-specific stem cell for cartilage engineering and regeneration.

    Jones, Brendan A; Pei, Ming

    2012-08-01

    Articular cartilage is difficult to heal once injury or disease occurs. Autologous chondrocyte transplantation is a biological treatment with good prognosis, but donor site morbidity and limited cell source are disadvantages. Currently, mesenchymal stem cells (MSCs) are a promising approach for cartilage regeneration. Despite there being various sources, the best candidate for cartilage regeneration is the one with the greatest chondrogenic potential and the least hypertrophic differentiation. These properties are able to insure that the regenerated tissue is hyaline cartilage of high quality. This review article will summarize relevant literature to justify synovium-derived stem cells (SDSCs) as a tissue-specific stem cell for chondrogenesis by comparing synovium and cartilage with respect to anatomical location and functional structure, comparing the growth characterization and chondrogenic capacity of SDSCs and MSCs, evaluating the application of SDSCs in regenerative medicine and diseases, and discussing potential future directions.

  2. Current Status and Future Development of Cell Transplantation Therapy for Periodontal Tissue Regeneration

    Yoshida, Toshiyuki; Washio, Kaoru; Iwata, Takanori; Okano, Teruo; Ishikawa, Isao

    2012-01-01

    It has been shown that stem cell transplantation can regenerate periodontal tissue, and several clinical trials involving transplantation of stem cells into human patients have already begun or are in preparation. However, stem cell transplantation therapy is a new technology, and the events following transplantation are poorly understood. Several studies have reported side effects and potential risks associated with stem cell transplantation therapy. To protect patients from such risks, governments have placed regulations on stem cell transplantation therapies. It is important for the clinicians to understand the relevant risks and governmental regulations. This paper describes the ongoing clinical studies, basic research, risks, and governmental controls related to stem cell transplantation therapy. Then, one clinical study is introduced as an example of a government-approved periodontal cell transplantation therapy. PMID:22315604

  3. Current Status and Future Development of Cell Transplantation Therapy for Periodontal Tissue Regeneration

    Toshiyuki Yoshida

    2012-01-01

    Full Text Available It has been shown that stem cell transplantation can regenerate periodontal tissue, and several clinical trials involving transplantation of stem cells into human patients have already begun or are in preparation. However, stem cell transplantation therapy is a new technology, and the events following transplantation are poorly understood. Several studies have reported side effects and potential risks associated with stem cell transplantation therapy. To protect patients from such risks, governments have placed regulations on stem cell transplantation therapies. It is important for the clinicians to understand the relevant risks and governmental regulations. This paper describes the ongoing clinical studies, basic research, risks, and governmental controls related to stem cell transplantation therapy. Then, one clinical study is introduced as an example of a government-approved periodontal cell transplantation therapy.

  4. Reactivation of X-irradiated cell material during limb regeneration in Urodeles Amphibians

    Desselle, J.C.

    1979-10-01

    In amputated members irradiated with X-rays the regeneration power is inhibited. This power is restored by grafts of healthy tissue in the irradiated members. The origin of the cell material of the restored regeneration blastema has been studied by an original labelling technique. The different amounts of DNA in the graft cells and those of the stump mark the graft cells during the regeneration process. It was shown that the graft causes a reactivation of the inhibited stump cells and the reactivation stages are the same as the activation stages of the member regenerating normally. It was also established that during restored regeneration the cell material implanted in the irradiated members contributes, by the 160th day of regeneration, 4.5% of the cartilaginous regenerate cells and 12% of the muscle cells. All the other regenerate cells are supplied by the cells of the stump; these are reactivated and together with the activated graft cells lead to the restitution of the amputated member [fr

  5. Neural stem cells promote nerve regeneration through IL12-induced Schwann cell differentiation.

    Lee, Don-Ching; Chen, Jong-Hang; Hsu, Tai-Yu; Chang, Li-Hsun; Chang, Hsu; Chi, Ya-Hui; Chiu, Ing-Ming

    2017-03-01

    Regeneration of injured peripheral nerves is a slow, complicated process that could be improved by implantation of neural stem cells (NSCs) or nerve conduit. Implantation of NSCs along with conduits promotes the regeneration of damaged nerve, likely because (i) conduit supports and guides axonal growth from one nerve stump to the other, while preventing fibrous tissue ingrowth and retaining neurotrophic factors; and (ii) implanted NSCs differentiate into Schwann cells and maintain a growth factor enriched microenvironment, which promotes nerve regeneration. In this study, we identified IL12p80 (homodimer of IL12p40) in the cell extracts of implanted nerve conduit combined with NSCs by using protein antibody array and Western blotting. Levels of IL12p80 in these conduits are 1.6-fold higher than those in conduits without NSCs. In the sciatic nerve injury mouse model, implantation of NSCs combined with nerve conduit and IL12p80 improves motor recovery and increases the diameter up to 4.5-fold, at the medial site of the regenerated nerve. In vitro study further revealed that IL12p80 stimulates the Schwann cell differentiation of mouse NSCs through the phosphorylation of signal transducer and activator of transcription 3 (Stat3). These results suggest that IL12p80 can trigger Schwann cell differentiation of mouse NSCs through Stat3 phosphorylation and enhance the functional recovery and the diameter of regenerated nerves in a mouse sciatic nerve injury model. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Dentin and dental pulp regeneration by the patient’s endogenous cells

    KIM, SAHNG G.; ZHENG, YING; ZHOU, JIAN; CHEN, MO; EMBREE, MILDRED C.; SONG, KAREN; JIANG, NAN; MAO, JEREMY J.

    2013-01-01

    The goal of regenerative endodontics is to restore the functions of the dental pulp–dentin complex. Two approaches are being applied toward dental pulp–dentin regeneration: cell transplantation and cell homing. The majority of previous approaches are based on cell transplantation by delivering ex vivo cultivated cells toward dental pulp or dentin regeneration. Many hurdles limit the clinical translation of cell transplantation such as the difficulty of acquiring and isolating viable cells, un...

  7. Intravenous Transplantation of Mesenchymal Stromal Cells to Enhance Peripheral Nerve Regeneration

    Stella M. Matthes

    2013-01-01

    Full Text Available Peripheral nerve injury is a common and devastating complication after trauma and can cause irreversible impairment or even complete functional loss of the affected limb. While peripheral nerve repair results in some axonal regeneration and functional recovery, the clinical outcome is not optimal and research continues to optimize functional recovery after nerve repair. Cell transplantation approaches are being used experimentally to enhance regeneration. Intravenous infusion of mesenchymal stromal cells (MSCs into spinal cord injury and stroke was shown to improve functional outcome. However, the repair potential of intravenously transplanted MSCs in peripheral nerve injury has not been addressed yet. Here we describe the impact of intravenously infused MSCs on functional outcome in a peripheral nerve injury model. Rat sciatic nerves were transected followed, by intravenous MSCs transplantation. Footprint analysis was carried out and 21 days after transplantation, the nerves were removed for histology. Labelled MSCs were found in the sciatic nerve lesion site after intravenous injection and regeneration was improved. Intravenously infused MSCs after acute peripheral nerve target the lesion site and survive within the nerve and the MSC treated group showed greater functional improvement. The results of study suggest that nerve repair with cell transplantation could lead to greater functional outcome.

  8. Effect of JNK inhibitor SP600125 on hair cell regeneration in zebrafish (Danio rerio) larvae

    Sun, Shaoyang; Wang, Xu; Li, Wenyan; Li, Huawei

    2016-01-01

    The c-Jun amino-terminal kinase (JNK) proteins are a subgroup of the mitogen-activated protein kinase family. They play a complex role in cell proliferation, survival, and apoptosis. Here, we report a novel role of JNK signalling in hair cell regeneration. We eliminated hair cells of 5-day post-fertilization zebrafish larvae using neomycin followed by JNK inhibition with SP600125. JNK inhibition strongly decreased the number of regenerated hair cells in response to neomycin damage. These changes were associated with reduced proliferation. JNK inhibition also increased cleaved caspase-3 activity and induced apoptosis in regenerating neuromasts. Finally, JNK inhibition with SP600125 decreased the expression of genes related to Wnt. Over-activation of the Wnt signalling pathway partly rescued the hair cell regeneration defects induced by JNK inhibition. Together, our findings provide novel insights into the function of JNK and show that JNK inhibition blocks hair cell regeneration by controlling the Wnt signalling pathway. PMID:27438150

  9. Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea

    Li, Wenyan; Chen, Yan; Zhang, Shasha; Tang, Mingliang; Sun, Shan; Chai, Renjie; Li, Huawei

    2016-01-01

    Hair cell (HC) loss is the main cause of permanent hearing loss in mammals. Previous studies have reported that in neonatal mice cochleae, Wnt activation promotes supporting cell (SC) proliferation and Notch inhibition promotes the trans-differentiation of SCs into HCs. However, Wnt activation alone fails to regenerate significant amounts of new HCs, Notch inhibition alone regenerates the HCs at the cost of exhausting the SC population, which leads to the death of the newly regenerated HCs. Mitotic HC regeneration might preserve the SC number while regenerating the HCs, which could be a better approach for long-term HC regeneration. We present a two-step gene manipulation, Wnt activation followed by Notch inhibition, to accomplish mitotic regeneration of HCs while partially preserving the SC number. We show that Wnt activation followed by Notch inhibition strongly promotes the mitotic regeneration of new HCs in both normal and neomycin-damaged cochleae while partially preserving the SC number. Lineage tracing shows that the majority of the mitotically regenerated HCs are derived specifically from the Lgr5+ progenitors with or without HC damage. Our findings suggest that the co-regulation of Wnt and Notch signaling might provide a better approach to mitotically regenerate HCs from Lgr5+ progenitor cells. PMID:27564256

  10. Heterogeneous fates and dynamic rearrangement of regenerative epidermis-derived cells during zebrafish fin regeneration.

    Shibata, Eri; Ando, Kazunori; Murase, Emiko; Kawakami, Atsushi

    2018-04-13

    The regenerative epidermis (RE) is a specialized tissue that plays an essential role in tissue regeneration. However, the fate of the RE during and after regeneration is unknown. In this study, we performed Cre- loxP -mediated cell fate tracking and revealed the fates of a major population of the RE cells that express fibronectin 1b ( fn1b ) during zebrafish fin regeneration. Our study showed that these RE cells are mainly recruited from the inter-ray epidermis, and that they follow heterogeneous cell fates. Early recruited cells contribute to initial wound healing and soon disappear by apoptosis, while the later recruited cells contribute to the regenerated epidermis. Intriguingly, many of these cells are also expelled from the regenerated tissue by a dynamic caudal movement of the epidermis over time, and in turn the loss of epidermal cells is replenished by a global self-replication of basal and suprabasal cells in fin. De-differentiation of non-basal epidermal cells into the basal epidermal cells did not occur during regeneration. Overall, our study reveals the heterogeneous fates of RE cells and a dynamic rearrangement of the epidermis during and after regeneration. © 2018. Published by The Company of Biologists Ltd.

  11. Human amniotic mesenchymal stromal cell transplantation improves endometrial regeneration in rodent models of intrauterine adhesions.

    Gan, Lu; Duan, Hua; Xu, Qian; Tang, Yi-Qun; Li, Jin-Jiao; Sun, Fu-Qing; Wang, Sha

    2017-05-01

    Intrauterine adhesion (IUA) is a common uterine cavity disease characterized by the unsatisfactory regeneration of damaged endometria. Recently, stem cell transplantation has been proposed to promote the recovery process. Here we investigated whether human amniotic mesenchymal stromal cells (hAMSCs), a valuable resource for transplantation therapy, could improve endometrial regeneration in rodent IUA models. Forty female Sprague-Dawley rats were randomly assigned to five groups: normal, sham-operated, mechanical injury, hAMSC transplantation, and negative control group. One week after intervention and transplantation, histological analyses were performed, and immunofluorescent and immunohistochemical expression of cell-specific markers and messenger RNA expression of cytokines were measured. Thicker endometria, increased gland numbers and fewer fibrotic areas were found in the hAMSC transplantation group compared with the mechanical injury group. Engraftment of hAMSCs was detected by the presence of anti-human nuclear antigen-positive cells in the endometrial glands of the transplantation uteri. Transplantation of hAMSCs significantly decreased messenger RNA levels of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β), and increased those of anti-inflammatory cytokines (basic fibroblast growth factor, and interleukin-6) compared with the injured uterine horns. Immunohistochemical expression of endometrial epithelial cells was revealed in specimens after hAMSC transplantation, whereas it was absent in the mechanically injured uteri. hAMSC transplantation promotes endometrial regeneration after injury in IUA rat models, possibly due to immunomodulatory properties. These cells provide a more easily accessible source of stem cells for future research into the impact of cell transplantation on damaged endometria. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  12. Discussion: Changes in Vocal Production and Auditory Perception after Hair Cell Regeneration.

    Ryals, Brenda M.; Dooling, Robert J.

    2000-01-01

    A bird study found that with sufficient time and training after hair cell and hearing loss and hair cell regeneration, the mature avian auditory system can accommodate input from a newly regenerated periphery sufficiently to allow for recognition of previously familiar vocalizations and the learning of new complex acoustic classifications.…

  13. Cells supporting long-term hemopoiesis in the culture are incapable of regeneration after irrdiation

    Deryugina, E.I.; Drize, N.I.; Chertkov, I.L.

    1987-01-01

    It has been revealed by competitive repopulation assay that hemopoietic stem cells capable of supporting long-term hemopoiesis in the culture failed to regenerate after irradiation. 19 weeks after irradiation with 4 Gy the content of hemopoietic stem cells was 0.5% normal, while regeneration of CFUs was achieved up to subnormal level

  14. IGFBP1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation.

    Lu, Jing; Liu, Ka-Cheuk; Schulz, Nadja; Karampelias, Christos; Charbord, Jérémie; Hilding, Agneta; Rautio, Linn; Bertolino, Philippe; Östenson, Claes-Göran; Brismar, Kerstin; Andersson, Olov

    2016-09-15

    There is great interest in therapeutically harnessing endogenous regenerative mechanisms to increase the number of β cells in people with diabetes. By performing whole-genome expression profiling of zebrafish islets, we identified 11 secreted proteins that are upregulated during β-cell regeneration. We then tested the proteins' ability to potentiate β-cell regeneration in zebrafish at supraphysiological levels. One protein, insulin-like growth factor (Igf) binding-protein 1 (Igfbp1), potently promoted β-cell regeneration by potentiating α- to β-cell transdifferentiation. Using various inhibitors and activators of the Igf pathway, we show that Igfbp1 exerts its regenerative effect, at least partly, by inhibiting Igf signaling. Igfbp1's effect on transdifferentiation appears conserved across species: Treating mouse and human islets with recombinant IGFBP1 in vitro increased the number of cells co-expressing insulin and glucagon threefold. Moreover, a prospective human study showed that having high IGFBP1 levels reduces the risk of developing type-2 diabetes by more than 85%. Thus, we identify IGFBP1 as an endogenous promoter of β-cell regeneration and highlight its clinical importance in diabetes. © 2016 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

  15. Role of Schwann cells in the regeneration of penile and peripheral nerves

    Lin Wang

    2015-01-01

    Full Text Available Schwann cells (SCs are the principal glia of the peripheral nervous system. The end point of SC development is the formation of myelinating and nonmyelinating cells which ensheath large and small diameter axons, respectively. They play an important role in axon regeneration after injury, including cavernous nerve injury that leads to erectile dysfunction (ED. Despite improvement in radical prostatectomy surgical techniques, many patients still suffer from ED postoperatively as surgical trauma causes traction injuries and local inflammatory changes in the neuronal microenvironment of the autonomic fibers innervating the penis resulting in pathophysiological alterations in the end organ. The aim of this review is to summarize contemporary evidence regarding: (1 the origin and development of SCs in the peripheral and penile nerve system; (2 Wallerian degeneration and SC plastic change following peripheral and penile nerve injury; (3 how SCs promote peripheral and penile nerve regeneration by secreting neurotrophic factors; (4 and strategies targeting SCs to accelerate peripheral nerve regeneration. We searched PubMed for articles related to these topics in both animal models and human research and found numerous studies suggesting that SCs could be a novel target for treatment of nerve injury-induced ED.

  16. Neural stem/progenitor cells are activated during tail regeneration in the leopard gecko (Eublepharis macularius).

    Gilbert, E A B; Vickaryous, M K

    2018-02-01

    As for many lizards, the leopard gecko (Eublepharis macularius) can self-detach its tail to avoid predation and then regenerate a replacement. The replacement tail includes a regenerated spinal cord with a simple morphology: an ependymal layer surrounded by nerve tracts. We hypothesized that cells within the ependymal layer of the original spinal cord include populations of neural stem/progenitor cells (NSPCs) that contribute to the regenerated spinal cord. Prior to tail loss, we performed a bromodeoxyuridine pulse-chase experiment and found that a subset of ependymal layer cells (ELCs) were label-retaining after a 140-day chase period. Next, we conducted a detailed spatiotemporal characterization of these cells before, during, and after tail regeneration. Our findings show that SOX2, a hallmark protein of NSPCs, is constitutively expressed by virtually all ELCs before, during, and after regeneration. We also found that during regeneration, ELCs express an expanded panel of NSPC and lineage-restricted progenitor cell markers, including MSI-1, SOX9, and TUJ1. Using electron microscopy, we determined that multiciliated, uniciliated, and biciliated cells are present, although the latter was only observed in regenerated spinal cords. Our results demonstrate that cells within the ependymal layer of the original, regenerating and fully regenerate spinal cord represent a heterogeneous population. These include radial glia comparable to Type E and Type B cells, and a neuronal-like population of cerebrospinal fluid-contacting cells. We propose that spinal cord regeneration in geckos represents a truncation of the restorative trajectory observed in some urodeles and teleosts, resulting in the formation of a structurally distinct replacement. © 2017 Wiley Periodicals, Inc.

  17. Feathers and Fins: Non-mammalian models for hair cell regeneration

    Brignull, Heather R.; Raible, David W.; Stone, Jennifer S.

    2009-01-01

    Death of mechanosensory cells in the inner ear results in two profound disabilities: hearing loss and balance disorders. Although mammals lack the capacity to regenerate hair cells, recent studies in mice and other rodents have offered valuable insight into strategies for stimulating hair cell regeneration in mammals. Investigations of model organisms that retain the ability to form new hair cells after embryogenesis, such as fish and chicks, are equally important and have provided clues as t...

  18. Attachment and growth of human bone marrow derived mesenchymal stem cells on regenerated antheraea pernyi silk fibroin films

    Luan Xiying [Institute of Medical Biotechnology, Jiangsu Province Key Laboratory of Stem Cell, Suzhou University, Suzhou 215007 (China); Wang Yong [Institute of Medical Biotechnology, Jiangsu Province Key Laboratory of Stem Cell, Suzhou University, Suzhou 215007 (China); Duan Xiang [Institute of Medical Biotechnology, Jiangsu Province Key Laboratory of Stem Cell, Suzhou University, Suzhou 215007 (China); Duan Qiaoyan [Institute of Medical Biotechnology, Jiangsu Province Key Laboratory of Stem Cell, Suzhou University, Suzhou 215007 (China); Li Mingzhong [School of Materials Engineering, Suzhou University, Suzhou 215006 (China); Lu Shenzhou [School of Materials Engineering, Suzhou University, Suzhou 215006 (China); Zhang Huanxiang [Institute of Medical Biotechnology, Jiangsu Province Key Laboratory of Stem Cell, Suzhou University, Suzhou 215007 (China); Zhang Xueguang [Institute of Medical Biotechnology, Jiangsu Province Key Laboratory of Stem Cell, Suzhou University, Suzhou 215007 (China)

    2006-12-15

    Silk fibroin of the silkworm Bombyx mori has been studied extensively, while the research on Antheraea pernyi silk fibroin (A. pernyi SF) in biomaterials is only at an early stage. In this study, the attachment, morphology, growth and phenotype of human bone marrow derived mesenchymal stem cells (hBMSCs) cultured on the regenerated A. pernyi SF films were studied in vitro. The results indicated that the attachment of hBMSCs on the regenerated A. pernyi SF films was almost the same as that on the collagen films. MTT and cell counting analyses demonstrated that the growth of hBMSCs on the regenerated A. pernyi SF films was better than that on controls. Moreover, electron scanning microscopy and fluorescence-activated cell sorting assays showed that the regenerated A. pernyi SF supported hBMSCs growth and functional maintenance compared with the controls. These data suggest that the regenerated A. pernyi SF, like Bombyx mori silk fibroin (B. mori SF) and collagen, can support hBMSCs attachment, growth and phenotypic maintenance, and has better biocompatibilities for hBMSCs in vitro culture.

  19. Attachment and growth of human bone marrow derived mesenchymal stem cells on regenerated antheraea pernyi silk fibroin films

    Luan Xiying; Wang Yong; Duan Xiang; Duan Qiaoyan; Li Mingzhong; Lu Shenzhou; Zhang Huanxiang; Zhang Xueguang

    2006-01-01

    Silk fibroin of the silkworm Bombyx mori has been studied extensively, while the research on Antheraea pernyi silk fibroin (A. pernyi SF) in biomaterials is only at an early stage. In this study, the attachment, morphology, growth and phenotype of human bone marrow derived mesenchymal stem cells (hBMSCs) cultured on the regenerated A. pernyi SF films were studied in vitro. The results indicated that the attachment of hBMSCs on the regenerated A. pernyi SF films was almost the same as that on the collagen films. MTT and cell counting analyses demonstrated that the growth of hBMSCs on the regenerated A. pernyi SF films was better than that on controls. Moreover, electron scanning microscopy and fluorescence-activated cell sorting assays showed that the regenerated A. pernyi SF supported hBMSCs growth and functional maintenance compared with the controls. These data suggest that the regenerated A. pernyi SF, like Bombyx mori silk fibroin (B. mori SF) and collagen, can support hBMSCs attachment, growth and phenotypic maintenance, and has better biocompatibilities for hBMSCs in vitro culture

  20. Full Length Research Paper Plant regeneration of Michelia ...

    Michelia champaca L. is a woody ornamental tree species which has high commercial value to be used as a basic material for perfume, cosmetic, and medicine. The development of an efficient plant regeneration system for M. champaca is essential for the production of Champaca planting material and precondition for ...

  1. Trophic Effects of Dental Pulp Stem Cells on Schwann Cells in Peripheral Nerve Regeneration.

    Yamamoto, Tsubasa; Osako, Yohei; Ito, Masataka; Murakami, Masashi; Hayashi, Yuki; Horibe, Hiroshi; Iohara, Koichiro; Takeuchi, Norio; Okui, Nobuyuki; Hirata, Hitoshi; Nakayama, Hidenori; Kurita, Kenichi; Nakashima, Misako

    2016-01-01

    Recently, mesenchymal stem cells have demonstrated a potential for neurotrophy and neurodifferentiation. We have recently isolated mobilized dental pulp stem cells (MDPSCs) using granulocyte-colony stimulating factor (G-CSF) gradient, which has high neurotrophic/angiogenic potential. The aim of this study is to investigate the effects of MDPSC transplantation on peripheral nerve regeneration. Effects of MDPSC transplantation were examined in a rat sciatic nerve defect model and compared with autografts and control conduits containing collagen scaffold. Effects of conditioned medium of MDPSCs were also evaluated in vitro. Transplantation of MDPSCs in the defect demonstrated regeneration of myelinated fibers, whose axons were significantly higher in density compared with those in autografts and control conduits only. Enhanced revascularization was also observed in the MDPSC transplants. The MDPSCs did not directly differentiate into Schwann cell phenotype; localization of these cells near Schwann cells induced several neurotrophic factors. Immunofluorescence labeling demonstrated reduced apoptosis and increased proliferation in resident Schwann cells in the MDPSC transplant compared with control conduits. These trophic effects of MDPSCs on proliferation, migration, and antiapoptosis in Schwann cells were further elucidated in vitro. The results demonstrate that MDPSCs promote axon regeneration through trophic functions, acting on Schwann cells, and promoting angiogenesis.

  2. Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

    Wertheimer, Tobias; Velardi, Enrico; Tsai, Jennifer; Cooper, Kirsten; Xiao, Shiyun; Kloss, Christopher C.; Ottmüller, Katja J.; Mokhtari, Zeinab; Brede, Christian; deRoos, Paul; Kinsella, Sinéad; Palikuqi, Brisa; Ginsberg, Michael; Young, Lauren F.; Kreines, Fabiana; Lieberman, Sophia R.; Lazrak, Amina; Guo, Peipei; Malard, Florent; Smith, Odette M.; Shono, Yusuke; Jenq, Robert R.; Hanash, Alan M.; Nolan, Daniel J.; Butler, Jason M.; Beilhack, Andreas; Manley, Nancy R.; Rafii, Shahin; Dudakov, Jarrod A; van den Brink, Marcel RM

    2018-01-01

    The thymus is extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood and this capacity diminishes considerably with age. Here we show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration, via their production of BMP4. ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signalling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1, a key transcription factor involved in TEC development, maintenance and regeneration; and its downstream targets such as Dll4, itself a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity. PMID:29330161

  3. Germline Transgenic Methods for Tracking Cells and Testing Gene Function during Regeneration in the Axolotl

    Khattak, Shahryar; Schuez, Maritta; Richter, Tobias; Knapp, Dunja; Haigo, Saori L.; Sandoval-Guzmán, Tatiana; Hradlikova, Kristyna; Duemmler, Annett; Kerney, Ryan; Tanaka, Elly M.

    2013-01-01

    The salamander is the only tetrapod that regenerates complex body structures throughout life. Deciphering the underlying molecular processes of regeneration is fundamental for regenerative medicine and developmental biology, but the model organism had limited tools for molecular analysis. We describe a comprehensive set of germline transgenic strains in the laboratory-bred salamander Ambystoma mexicanum (axolotl) that open up the cellular and molecular genetic dissection of regeneration. We demonstrate tissue-dependent control of gene expression in nerve, Schwann cells, oligodendrocytes, muscle, epidermis, and cartilage. Furthermore, we demonstrate the use of tamoxifen-induced Cre/loxP-mediated recombination to indelibly mark different cell types. Finally, we inducibly overexpress the cell-cycle inhibitor p16INK4a, which negatively regulates spinal cord regeneration. These tissue-specific germline axolotl lines and tightly inducible Cre drivers and LoxP reporter lines render this classical regeneration model molecularly accessible. PMID:24052945

  4. Osteoblast Production by Reserved Progenitor Cells in Zebrafish Bone Regeneration and Maintenance.

    Ando, Kazunori; Shibata, Eri; Hans, Stefan; Brand, Michael; Kawakami, Atsushi

    2017-12-04

    Mammals cannot re-form heavily damaged bones as in large fracture gaps, whereas zebrafish efficiently regenerate bones even after amputation of appendages. However, the source of osteoblasts that mediate appendage regeneration is controversial. Several studies in zebrafish have shown that osteoblasts are generated by dedifferentiation of existing osteoblasts at injured sites, but other observations suggest that de novo production of osteoblasts also occurs. In this study, we found from cell-lineage tracing and ablation experiments that a group of cells reserved in niches serves as osteoblast progenitor cells (OPCs) and has a significant role in fin ray regeneration. Besides regeneration, OPCs also supply osteoblasts for normal bone maintenance. We further showed that OPCs are derived from embryonic somites, as is the case with embryonic osteoblasts, and are replenished from mesenchymal precursors in adult zebrafish. Our findings reveal that reserved progenitors are a significant and complementary source of osteoblasts for zebrafish bone regeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Isolation, Characterization, and Differentiation of Stem Cells for Cartilage Regeneration

    Beane, Olivia S.; Darling, Eric M.

    2012-01-01

    The goal of tissue engineering is to create a functional replacement for tissues damaged by injury or disease. In many cases, impaired tissues cannot provide viable cells, leading to the investigation of stem cells as a possible alternative. Cartilage, in particular, may benefit from the use of stem cells since the tissue has low cellularity and cannot effectively repair itself. To address this need, researchers are investigating the chondrogenic capabilities of several multipotent stem cell ...

  6. Potential of laryngeal muscle regeneration using induced pluripotent stem cell-derived skeletal muscle cells.

    Dirja, Bayu Tirta; Yoshie, Susumu; Ikeda, Masakazu; Imaizumi, Mitsuyoshi; Nakamura, Ryosuke; Otsuki, Koshi; Nomoto, Yukio; Wada, Ikuo; Hazama, Akihiro; Omori, Koichi

    2016-01-01

    Conclusion Induced pluripotent stem (iPS) cells may be a new potential cell source for laryngeal muscle regeneration in the treatment of vocal fold atrophy after recurrent laryngeal nerve paralysis. Objectives Unilateral vocal fold paralysis can lead to degeneration, atrophy, and loss of force of the thyroarytenoid muscle. At present, there are some treatments such as thyroplasty, arytenoid adduction, and vocal fold injection. However, such treatments cannot restore reduced mass of the thyroarytenoid muscle. iPS cells have been recognized as supplying a potential resource for cell transplantation. The aim of this study was to assess the effectiveness of the use of iPS cells for the regeneration of laryngeal muscle through the evaluation of both in vitro and in vivo experiments. Methods Skeletal muscle cells were generated from tdTomato-labeled iPS cells using embryoid body formation. Differentiation into skeletal muscle cells was analyzed by gene expression and immunocytochemistry. The tdTomato-labeled iPS cell-derived skeletal muscle cells were transplanted into the left atrophied thyroarytenoid muscle. To evaluate the engraftment of these cells after transplantation, immunohistochemistry was performed. Results The tdTomato-labeled iPS cells were successfully differentiated into skeletal muscle cells through an in vitro experiment. These cells survived in the atrophied thyroarytenoid muscle after transplantation.

  7. Regeneration of articular cartilage by adipose tissue derived mesenchymal stem cells: perspectives from stem cell biology and molecular medicine.

    Wu, Ling; Cai, Xiaoxiao; Zhang, Shu; Karperien, Marcel; Lin, Yunfeng

    2013-05-01

    Adipose-derived stem cells (ASCs) have been discovered for more than a decade. Due to the large numbers of cells that can be harvested with relatively little donor morbidity, they are considered to be an attractive alternative to bone marrow derived mesenchymal stem cells. Consequently, isolation and differentiation of ASCs draw great attention in the research of tissue engineering and regenerative medicine. Cartilage defects cause big therapeutic problems because of their low self-repair capacity. Application of ASCs in cartilage regeneration gives hope to treat cartilage defects with autologous stem cells. In recent years, a lot of studies have been performed to test the possibility of using ASCs to re-construct damaged cartilage tissue. In this article, we have reviewed the most up-to-date articles utilizing ASCs for cartilage regeneration in basic and translational research. Our topic covers differentiation of adipose tissue derived mesenchymal stem cells into chondrocytes, increased cartilage formation by co-culture of ASCs with chondrocytes and enhancing chondrogenic differentiation of ASCs by gene manipulation. Copyright © 2012 Wiley Periodicals, Inc.

  8. Cell Fate of Müller Cells During Photoreceptor Regeneration in an N-Methyl-N-nitrosourea-Induced Retinal Degeneration Model of Zebrafish.

    Ogai, Kazuhiro; Hisano, Suguru; Sugitani, Kayo; Koriyama, Yoshiki; Kato, Satoru

    2016-01-01

    Zebrafish can regenerate several organs such as the tail fin, heart, central nervous system, and photoreceptors. Very recently, a study has demonstrated the photoreceptor regeneration in the alkylating agent N-methyl-N-nitrosourea (MNU)-induced retinal degeneration (RD) zebrafish model, in which whole photoreceptors are lost within a week after MNU treatment and then regenerated within a month. The research has also shown massive proliferation of Müller cells within a week. To address the question of whether proliferating Müller cells are the source of regenerating photoreceptors, which remains unknown in the MNU-induced zebrafish RD model, we employed a BrdU pulse-chase technique to label the proliferating cells within a week after MNU treatment. As a result of the BrdU pulse-chase technique, a number of BrdU(+) cells were observed in the outer nuclear layer as well as the inner nuclear layer. This implies that regenerating photoreceptors are derived from proliferating Müller cells in the zebrafish MNU-induced RD model.

  9. Purified Human Dental Pulp Stem Cells Promote Osteogenic Regeneration.

    Yasui, T; Mabuchi, Y; Toriumi, H; Ebine, T; Niibe, K; Houlihan, D D; Morikawa, S; Onizawa, K; Kawana, H; Akazawa, C; Suzuki, N; Nakagawa, T; Okano, H; Matsuzaki, Y

    2016-02-01

    Human dental pulp stem/progenitor cells (hDPSCs) are attractive candidates for regenerative therapy because they can be easily expanded to generate colony-forming unit-fibroblasts (CFU-Fs) on plastic and the large cell numbers required for transplantation. However, isolation based on adherence to plastic inevitably changes the surface marker expression and biological properties of the cells. Consequently, little is currently known about the original phenotypes of tissue precursor cells that give rise to plastic-adherent CFU-Fs. To better understand the in vivo functions and translational therapeutic potential of hDPSCs and other stem cells, selective cell markers must be identified in the progenitor cells. Here, we identified a dental pulp tissue-specific cell population based on the expression profiles of 2 cell-surface markers LNGFR (CD271) and THY-1 (CD90). Prospectively isolated, dental pulp-derived LNGFR(Low+)THY-1(High+) cells represent a highly enriched population of clonogenic cells--notably, the isolated cells exhibited long-term proliferation and multilineage differentiation potential in vitro. The cells also expressed known mesenchymal cell markers and promoted new bone formation to heal critical-size calvarial defects in vivo. These findings suggest that LNGFR(Low+)THY-1(High+) dental pulp-derived cells provide an excellent source of material for bone regenerative strategies. © International & American Associations for Dental Research 2015.

  10. NGF induces adult stem Leydig cells to proliferate and differentiate during Leydig cell regeneration.

    Zhang, Lei; Wang, Huaxi; Yang, Yan; Liu, Hui; Zhang, Qihao; Xiang, Qi; Ge, Renshan; Su, Zhijian; Huang, Yadong

    2013-06-28

    Nerve growth factor (NGF) has been reported to be involved in male reproductive physiology. However, few reports have described the activity of NGF during Leydig cell development. The objective of the present study was to examine the role of NGF during stem-Leydig-cell (SLC) regeneration. We investigated the effects of NGF on Leydig-cell (LC) regeneration by measuring mRNA levels in the adult rat testis after ethane dimethanesulfonate (EDS) treatment. Furthermore, we used the established organ culture model of rat seminiferous tubules to examine the regulation of NGF during SLC proliferation and differentiation using EdU staining, real-time PCR and western blotting. Progenitor Leydig cells (PLCs) and immature Leydig cells (ILCs) were also used to investigate the effects of NGF on LCs at different developmental stages. NGF mRNA levels changed significantly during Leydig-cell regeneration in vivo. In vitro, NGF significantly promoted the proliferation of stem Leydig cells and also induced steroidogenic enzyme gene expression and 3β-HSD protein expression. The data from PLCs and ILCs showed that NGF could increase Cyclin D1 and Hsd 17b3 mRNA levels in PLCs and Cyclin D1 mRNA levels in ILCs. These results indicate that NGF may play an important role during LC regeneration by regulating the proliferation and differentiation of LCs at different developmental stages, from SLCs to PLCs and from PLCs to ILCs. The discovery of this effect of NGF on Leydig cells will provide useful information for developing new potential therapies for PADAM (Partial Androgen Deficiency in the Aging Male). Copyright © 2013 Elsevier Inc. All rights reserved.

  11. A myogenic precursor cell that could contribute to regeneration in zebrafish and its similarity to the satellite cell.

    Siegel, Ashley L; Gurevich, David B; Currie, Peter D

    2013-09-01

    The cellular basis for mammalian muscle regeneration has been an area of intense investigation over recent decades. The consensus is that a specialized self-renewing stem cell, termed the satellite cell, plays a major role during the process of regeneration in amniotes. How broadly this mechanism is deployed within the vertebrate phylogeny remains an open question. A lack of information on the role of cells analogous to the satellite cell in other vertebrate systems is even more unexpected given the fact that satellite cells were first designated in frogs. An intriguing aspect of this debate is that a number of amphibia and many fish species exhibit epimorphic regenerative processes in specific tissues, whereby regeneration occurs by the dedifferentiation of the damaged tissue, without deploying specialized stem cell populations analogous to satellite cells. Hence, it is feasible that a cellular process completely distinct from that deployed during mammalian muscle regeneration could operate in species capable of epimorphic regeneration. In this minireview, we examine the evidence for the broad phylogenetic distribution of satellite cells. We conclude that, in the vertebrates examined so far, epimorphosis does not appear to be deployed during muscle regeneration, and that analogous cells expressing similar marker genes to satellite cells appear to be deployed during the regenerative process. However, the functional definition of these cells as self-renewing muscle stem cells remains a final hurdle to the definition of the satellite cell as a generic vertebrate cell type. © 2013 FEBS.

  12. Cartilage and bone cells do not participate in skeletal regeneration in Ambystoma mexicanum limbs.

    McCusker, Catherine D; Diaz-Castillo, Carlos; Sosnik, Julian; Q Phan, Anne; Gardiner, David M

    2016-08-01

    The Mexican Axolotl is one of the few tetrapod species that is capable of regenerating complete skeletal elements in injured adult limbs. Whether the skeleton (bone and cartilage) plays a role in the patterning and contribution to the skeletal regenerate is currently unresolved. We tested the induction of pattern formation, the effect on cell proliferation, and contributions of skeletal tissues (cartilage, bone, and periosteum) to the regenerating axolotl limb. We found that bone tissue grafts from transgenic donors expressing GFP fail to induce pattern formation and do not contribute to the newly regenerated skeleton. Periosteum tissue grafts, on the other hand, have both of these activities. These observations reveal that skeletal tissue does not contribute to the regeneration of skeletal elements; rather, these structures are patterned by and derived from cells of non-skeletal connective tissue origin. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Stem cells in retinal regeneration: past, present and future.

    Ramsden, Conor M; Powner, Michael B; Carr, Amanda-Jayne F; Smart, Matthew J K; da Cruz, Lyndon; Coffey, Peter J

    2013-06-01

    Stem cell therapy for retinal disease is under way, and several clinical trials are currently recruiting. These trials use human embryonic, foetal and umbilical cord tissue-derived stem cells and bone marrow-derived stem cells to treat visual disorders such as age-related macular degeneration, Stargardt's disease and retinitis pigmentosa. Over a decade of analysing the developmental cues involved in retinal generation and stem cell biology, coupled with extensive surgical research, have yielded differing cellular approaches to tackle these retinopathies. Here, we review these various stem cell-based approaches for treating retinal diseases and discuss future directions and challenges for the field.

  14. Castration-Resistant Lgr5+ Cells Are Long-Lived Stem Cells Required for Prostatic Regeneration

    Bu-er Wang

    2015-05-01

    Full Text Available The adult prostate possesses a significant regenerative capacity that is of great interest for understanding adult stem cell biology. We demonstrate that leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5 is expressed in a rare population of prostate epithelial progenitor cells, and a castration-resistant Lgr5+ population exists in regressed prostate tissue. Genetic lineage tracing revealed that Lgr5+ cells and their progeny are primarily luminal. Lgr5+ castration-resistant cells are long lived and upon regeneration, both luminal Lgr5+ cells and basal Lgr5+ cells expand. Moreover, single Lgr5+ cells can generate multilineage prostatic structures in renal transplantation assays. Additionally, Lgr5+ cell depletion revealed that the regenerative potential of the castrated adult prostate depends on Lgr5+ cells. Together, these data reveal insights into the cellular hierarchy of castration-resistant Lgr5+ cells, indicate a requirement for Lgr5+ cells during prostatic regeneration, and identify an Lgr5+ adult stem cell population in the prostate.

  15. A Review of Gene Delivery and Stem Cell Based Therapies for Regenerating Inner Ear Hair Cells

    Michael S. Detamore

    2011-09-01

    Full Text Available Sensory neural hearing loss and vestibular dysfunction have become the most common forms of sensory defects, affecting millions of people worldwide. Developing effective therapies to restore hearing loss is challenging, owing to the limited regenerative capacity of the inner ear hair cells. With recent advances in understanding the developmental biology of mammalian and non-mammalian hair cells a variety of strategies have emerged to restore lost hair cells are being developed. Two predominant strategies have developed to restore hair cells: transfer of genes responsible for hair cell genesis and replacement of missing cells via transfer of stem cells. In this review article, we evaluate the use of several genes involved in hair cell regeneration, the advantages and disadvantages of the different viral vectors employed in inner ear gene delivery and the insights gained from the use of embryonic, adult and induced pluripotent stem cells in generating inner ear hair cells. Understanding the role of genes, vectors and stem cells in therapeutic strategies led us to explore potential solutions to overcome the limitations associated with their use in hair cell regeneration.

  16. A review of gene delivery and stem cell based therapies for regenerating inner ear hair cells.

    Devarajan, Keerthana; Staecker, Hinrich; Detamore, Michael S

    2011-09-13

    Sensory neural hearing loss and vestibular dysfunction have become the most common forms of sensory defects, affecting millions of people worldwide. Developing effective therapies to restore hearing loss is challenging, owing to the limited regenerative capacity of the inner ear hair cells. With recent advances in understanding the developmental biology of mammalian and non-mammalian hair cells a variety of strategies have emerged to restore lost hair cells are being developed. Two predominant strategies have developed to restore hair cells: transfer of genes responsible for hair cell genesis and replacement of missing cells via transfer of stem cells. In this review article, we evaluate the use of several genes involved in hair cell regeneration, the advantages and disadvantages of the different viral vectors employed in inner ear gene delivery and the insights gained from the use of embryonic, adult and induced pluripotent stem cells in generating inner ear hair cells. Understanding the role of genes, vectors and stem cells in therapeutic strategies led us to explore potential solutions to overcome the limitations associated with their use in hair cell regeneration.

  17. HEXIM1 controls satellite cell expansion after injury to regulate skeletal muscle regeneration

    Hong, Peng; Chen, Kang; Huang, Bihui; Liu, Min; Cui, Miao; Rozenberg, Inna; Chaqour, Brahim; Pan, Xiaoyue; Barton, Elisabeth R.; Jiang, Xian-Cheng; Siddiqui, M.A.Q.

    2012-01-01

    The native capacity of adult skeletal muscles to regenerate is vital to the recovery from physical injuries and dystrophic diseases. Currently, the development of therapeutic interventions has been hindered by the complex regulatory network underlying the process of muscle regeneration. Using a mouse model of skeletal muscle regeneration after injury, we identified hexamethylene bisacetamide inducible 1 (HEXIM1, also referred to as CLP-1), the inhibitory component of the positive transcription elongation factor b (P-TEFb) complex, as a pivotal regulator of skeletal muscle regeneration. Hexim1-haplodeficient muscles exhibited greater mass and preserved function compared with those of WT muscles after injury, as a result of enhanced expansion of satellite cells. Transplanted Hexim1-haplodeficient satellite cells expanded and improved muscle regeneration more effectively than WT satellite cells. Conversely, HEXIM1 overexpression restrained satellite cell proliferation and impeded muscle regeneration. Mechanistically, dissociation of HEXIM1 from P-TEFb and subsequent activation of P-TEFb are required for satellite cell proliferation and the prevention of early myogenic differentiation. These findings suggest a crucial role for the HEXIM1/P-TEFb pathway in the regulation of satellite cell–mediated muscle regeneration and identify HEXIM1 as a potential therapeutic target for degenerative muscular diseases. PMID:23023707

  18. Role of adenosine signalling and metabolism in β-cell regeneration

    Andersson, Olov, E-mail: olov.andersson@ki.se

    2014-02-01

    Glucose homeostasis, which is controlled by the endocrine cells of the pancreas, is disrupted in both type I and type II diabetes. Deficiency in the number of insulin-producing β cells – a primary cause of type I diabetes and a secondary contributor of type II diabetes – leads to hyperglycemia and hence an increase in the need for insulin. Although diabetes can be controlled with insulin injections, a curative approach is needed. A potential approach to curing diabetes involves regenerating the β-cell mass, e.g. by increasing β-cell proliferation, survival, neogenesis or transdifferentiation. The nucleoside adenosine and its cognate nucleotide ATP have long been known to affect insulin secretion, but have more recently been shown to increase β-cell proliferation during homeostatic control and regeneration of the β-cell mass. Adenosine is also known to have anti-inflammatory properties, and agonism of adenosine receptors can promote the survival of β-cells in an inflammatory microenvironment. In this review, both intracellular and extracellular mechanisms of adenosine and ATP are discussed in terms of their established and putative effects on β-cell regeneration. - Highlights: • A potential way to cure diabetes is to regenerate the β-cell mass by promoting cell survival, proliferation or neogenesis. • Adenosine may promote β-cell regeneration through several cellular mechanisms. • Adenosine and its cognate nucleotide ATP can each promote β-cell proliferation. • Do adenosine and ATP interact in promoting β-cell proliferation?.

  19. Role of adenosine signalling and metabolism in β-cell regeneration

    Andersson, Olov

    2014-01-01

    Glucose homeostasis, which is controlled by the endocrine cells of the pancreas, is disrupted in both type I and type II diabetes. Deficiency in the number of insulin-producing β cells – a primary cause of type I diabetes and a secondary contributor of type II diabetes – leads to hyperglycemia and hence an increase in the need for insulin. Although diabetes can be controlled with insulin injections, a curative approach is needed. A potential approach to curing diabetes involves regenerating the β-cell mass, e.g. by increasing β-cell proliferation, survival, neogenesis or transdifferentiation. The nucleoside adenosine and its cognate nucleotide ATP have long been known to affect insulin secretion, but have more recently been shown to increase β-cell proliferation during homeostatic control and regeneration of the β-cell mass. Adenosine is also known to have anti-inflammatory properties, and agonism of adenosine receptors can promote the survival of β-cells in an inflammatory microenvironment. In this review, both intracellular and extracellular mechanisms of adenosine and ATP are discussed in terms of their established and putative effects on β-cell regeneration. - Highlights: • A potential way to cure diabetes is to regenerate the β-cell mass by promoting cell survival, proliferation or neogenesis. • Adenosine may promote β-cell regeneration through several cellular mechanisms. • Adenosine and its cognate nucleotide ATP can each promote β-cell proliferation. • Do adenosine and ATP interact in promoting β-cell proliferation?

  20. Gradual regeneration of mouse testicular stem cells after exposure to ionizing radiation

    Meistrich, M.L.; Hunter, N.R.; Suzuki, N.; Trostle, P.K.; Withers, H.R.

    1978-01-01

    The regeneration of mouse testicular stem cells during 60 weeks after exposure to 600 or 1200 rad of γ radiation was examined. Restoration of spermatogenesis depended on stem cell survival, regeneration, and differentiation. Several assays were employed to measure the number of stem cells and their ability to repopulate the seminiferous epithelium as follows. Assay 1: The percentage of repopulated tubular cross sections was determined histologically at various times after irradiation. Assay 2: Mice were irradiated and, after given time intervals to allow for regeneration of stem cell numbers, a second dose was given. The percentage of repopulated tubular cross sections was determined 5 weeks later. Assay 3: The ability of the stem cells to produce spermatocytes and spermatids was assayed by the levels of the germ cell specific isoenzyme, LDH-X. Assay 4: The ability of the stem cells to produce sperm was assayed by the number of sperm heads in the testes. In addition, the ability of the stem cells to produce functional spermatozoa was measured by the fertility of the animals. The results obtained were as follows. All assays demonstrated that gradual regeneration of stem cell number occurred simultaneously with repopulation of the seminiferous epithelium by differentiating cells derived from stem cells. The regeneration kinetics of stem cells followed an exponential increase approaching a dose-dependent plateau below the level prior to irradiation. The doubling time for stem cells during the exponential portion was about 2 weeks. The regeneration of stem cell number after depletion by irradiation was gradual and incomplete, and only partially restored spermatogenesis. Correlation of regeneration with fertility data demonstrated that fertility was reestablished when sperm production returned to about 15% of control levels

  1. Contribution of different bone marrow-derived cell types in endometrial regeneration using an irradiated murine model.

    Gil-Sanchis, Claudia; Cervelló, Irene; Khurana, Satish; Faus, Amparo; Verfaillie, Catherine; Simón, Carlos

    2015-06-01

    To study the involvement of seven types of bone marrow-derived cells (BMDCs) in the endometrial regeneration in mice after total body irradiation. Prospective experimental animal study. University research laboratories. β-Actin-green fluorescent protein (GFP) transgenic C57BL/6-Tg (CAG-EGFP) and C57BL/6J female mice. The BMDCs were isolated from CAG-EGFP mice: unfractionated bone marrow cells, hematopoietic progenitor cells, endothelial progenitor cells (EPCs), and mesenchymal stem cells (MSCs). In addition three murine GFP(+) cell lines were used: mouse Oct4 negative BMDC multipotent adult progenitor cells (mOct4(-)BM-MAPCs), BMDC hypoblast-like stem cells (mOct4(+) BM-HypoSCs), and MSCs. All cell types were injected through the tail vein of 9 Gy-irradiated C57BL/6J female mice. Flow cytometry, cell culture, bone marrow transplantation assays, histologic evaluation, immunohistochemistry, proliferation, apoptosis, and statistical analysis. After 12 weeks, histologic analysis revealed that uteri of mice with mOct4(-)BM-MAPCs and MSC line were significantly smaller than uteri of mice with uncultured BMDCs or mOct4(+) BM-HypoSCs. The percentage of engrafted GFP(+) cells ranged from 0.13%-4.78%. Expression of Ki-67 was lower in all uteri from BMDCs treated mice than in the control, whereas TUNEL(+) cells were increased in the EPCs and mOct4(+)BM-HypoSCs groups. Low number of some BMDCs can be found in regenerating endometrium, including stromal, endotelial, and epithelial compartments. Freshly isolated MSCs and EPCs together with mOct4(+) BM-HypoSCs induced the greatest degree of regeneration, whereas culture isolated MSCs and mOct4(-)BM-MAPCs transplantation may have an inhibitory effect on endometrial regeneration. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  2. Exploiting endogenous fibrocartilage stem cells to regenerate cartilage and repair joint injury

    Embree, Mildred C.; Chen, Mo; Pylawka, Serhiy; Kong, Danielle; Iwaoka, George M.; Kalajzic, Ivo; Yao, Hai; Shi, Chancheng; Sun, Dongming; Sheu, Tzong-Jen; Koslovsky, David A.; Koch, Alia; Mao, Jeremy J.

    2016-01-01

    Tissue regeneration using stem cell-based transplantation faces many hurdles. Alternatively, therapeutically exploiting endogenous stem cells to regenerate injured or diseased tissue may circumvent these challenges. Here we show resident fibrocartilage stem cells (FCSCs) can be used to regenerate and repair cartilage. We identify FCSCs residing within the superficial zone niche in the temporomandibular joint (TMJ) condyle. A single FCSC spontaneously generates a cartilage anlage, remodels into bone and organizes a haematopoietic microenvironment. Wnt signals deplete the reservoir of FCSCs and cause cartilage degeneration. We also show that intra-articular treatment with the Wnt inhibitor sclerostin sustains the FCSC pool and regenerates cartilage in a TMJ injury model. We demonstrate the promise of exploiting resident FCSCs as a regenerative therapeutic strategy to substitute cell transplantation that could be beneficial for patients suffering from fibrocartilage injury and disease. These data prompt the examination of utilizing this strategy for other musculoskeletal tissues. PMID:27721375

  3. β-Cell dedifferentiation, reduced duct cell plasticity, and impaired β-cell mass regeneration in middle-aged rats.

    Téllez, Noèlia; Vilaseca, Marina; Martí, Yasmina; Pla, Arturo; Montanya, Eduard

    2016-09-01

    Limitations in β-cell regeneration potential in middle-aged animals could contribute to the increased risk to develop diabetes associated with aging. We investigated β-cell regeneration of middle-aged Wistar rats in response to two different regenerative stimuli: partial pancreatectomy (Px + V) and gastrin administration (Px + G). Pancreatic remnants were analyzed 3 and 14 days after surgery. β-Cell mass increased in young animals after Px and was further increased after gastrin treatment. In contrast, β-cell mass did not change after Px or after gastrin treatment in middle-aged rats. β-Cell replication and individual β-cell size were similarly increased after Px in young and middle-aged animals, and β-cell apoptosis was not modified. Nuclear immunolocalization of neurog3 or nkx6.1 in regenerative duct cells, markers of duct cell plasticity, was increased in young but not in middle-aged Px rats. The pancreatic progenitor-associated transcription factors neurog3 and sox9 were upregulated in islet β-cells of middle-aged rats and further increased after Px. The percentage of chromogranin A+/hormone islet cells was significantly increased in the pancreases of middle-aged Px rats. In summary, the potential for compensatory β-cell hyperplasia and hypertrophy was retained in middle-aged rats, but β-cell dedifferentiation and impaired duct cell plasticity limited β-cell regeneration. Copyright © 2016 the American Physiological Society.

  4. Neuromuscular Regeneration: Perspective on the Application of Mesenchymal Stem Cells and Their Secretion Products

    Ana Rita Caseiro

    2016-01-01

    Full Text Available Mesenchymal stem cells are posing as a promising character in the most recent therapeutic strategies and, since their discovery, extensive knowledge on their features and functions has been gained. In recent years, innovative sources have been disclosed in alternative to the bone marrow, conveying their associated ethical concerns and ease of harvest, such as the umbilical cord tissue and the dental pulp. These are also amenable of cryopreservation and thawing for desired purposes, in benefit of the donor itself or other patients in pressing need. These sources present promising possibilities in becoming useful cell sources for therapeutic applications in the forthcoming years. Effective and potential applications of these cellular-based strategies for the regeneration of peripheral nerve are overviewed, documenting recent advances and identified issues for this research area in the near future. Finally, besides the differentiation capacities attributed to mesenchymal stem cells, advances in the recognition of their effective mode of action in the regenerative theatre have led to a new area of interest: the mesenchymal stem cells’ secretome. The paracrine modulatory pathway appears to be a major mechanism by which these are beneficial to nerve regeneration and comprehension on the specific growth factors, cytokine, and extracellular molecules secretion profiles is therefore of great interest.

  5. THE POTENTIAL ROLE OF ENDOGENOUS STEM CELLS IN REGENERATION OF THE INNER EAR

    Martinez-Monedero, Rodrigo; Oshima, Kazuo; Heller, Stefan; Edge, Albert S.B.

    2007-01-01

    Stem cells in various mammalian tissues retain the capacity to renew themselves and may be able to restore damaged tissue. Their existence has been proven by genetic tracer studies that demonstrate their differentiation into multiple tissue types and by their ability to self-renew through proliferation. Stem cells from the adult nervous system proliferate to form clonal floating colonies called spheres in vitro, and recent studies have demonstrated sphere formation by cells in the cochlea in addition to the vestibular system and the auditory ganglia, indicating that these tissues contain cells with stem cell properties. The presence of stem cells in the inner ear raises the hope of regeneration of mammalian inner ear cells but is difficult to correlate with the lack spontaneous regeneration seen in the inner ear after tissue damage. Loss of stem cells postnatally in the cochlea may correlate with the loss of regenerative capacity and may limit our ability to stimulate regeneration. Retention of sphere forming capacity in adult vestibular tissues suggests that the limited capacity for repair may be attributed to the continued presence of progenitor cells. Future strategies for regeneration must consider the distribution of endogenous stem cells in the inner ear and whether cells with the capacity for regeneration are retained. PMID:17321086

  6. A novel shell-structure cell microcarrier (SSCM) for cell transplantation and bone regeneration medicine.

    Su, Kai; Gong, Yihong; Wang, Chunming; Wang, Dong-An

    2011-06-01

    The present study aims to develop a novel open and hollow shell-structure cell microcarrier (SSCM) to improve the anchorage-dependent cell (ADC) loading efficiency, increase the space for cell proliferation and tissue regeneration, and better propel its therapeutic effects. Gelatin particles were prepared with oil/water/oil (o/w/o) technique and modified by an adjustable surface crosslinking technique and subsequent release of uncrosslinked material. Optical microscopy and scanning electron microscopy (SEM) were utilized to observe the morphologies of the microcarriers. Cell loading tests were performed to evaluate the biocompatibilities and effect on osteogenesis of SSCM. SSCMs were successfully fabricated via the surface technique. The shell-structure could allow the cell to attach and grow on both outer and inner surface of sphere and provide adequate space for cell proliferation and extracellular matrix (ECM) secretion. The cell loading rate, proliferation rate and osteogenesis-related gene expressions on the SSCMs were higher than those on the spherical gelatin microcarriers. The outstanding performance of injectable SSCMs endowed with favorable micro-structure, desirable cytocompatibility and enhanced cell affinity makes them as a good choice as cell delivery vehicle for transplanting therapeutic cells towards the scope of tissue regeneration.

  7. Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration

    Ohki, Makiko; Ohki, Yuichi; Ishihara, Makoto

    2010-01-01

    tissue regeneration is not well understood. Bone marrow (BM)-derived myeloid cells facilitate angiogenesis during tissue regeneration. Here, we report that a serpin-resistant form of tPA by activating the extracellular proteases matrix metalloproteinase-9 and plasmin expands the myeloid cell pool......-A. Remarkably, transplantation of BM-derived tPA-mobilized CD11b(+) cells and VEGFR-1(+) cells, but not carrier-mobilized cells or CD11b(-) cells, accelerates neovascularization and ischemic tissue regeneration. Inhibition of VEGF signaling suppresses tPA-induced neovascularization in a model of hind limb...... and mobilizes CD45(+)CD11b(+) proangiogenic, myeloid cells, a process dependent on vascular endothelial growth factor-A (VEGF-A) and Kit ligand signaling. tPA improves the incorporation of CD11b(+) cells into ischemic tissues and increases expression of neoangiogenesis-related genes, including VEGF...

  8. Eye absence does not regulate planarian stem cells during eye regeneration

    LoCascio, Samuel A.; Lapan, Sylvain W.; Reddien, Peter W.

    2017-01-01

    Dividing cells called neoblasts contain pluripotent stem cells and drive planarian flatworm regeneration from diverse injuries. A long-standing question is whether neoblasts directly sense and respond to the identity of missing tissues during regeneration. We used the eye to investigate this question. Surprisingly, eye removal was neither sufficient nor necessary for neoblasts to increase eye progenitor production. Neoblasts normally increase eye progenitor production following decapitation, ...

  9. Mesenchymal Stem Cell Therapy for Nerve Regeneration and Immunomodulation after Composite Tissue Allotransplantation

    2012-02-01

    10-1-0927 TITLE: Mesenchymal Stem Cell Therapy for Nerve Regeneration and Immunomodulation after Composite Tissue Allotransplantation...immunosuppression. Bone Marrow Derived Mesenchymal stem cells (BM-MSCs) are pluripotent cells, capable of differentiation along multiple mesenchymal lineages into...As part of implemented transition from University of Pittsburgh to Johns Hopkins University, we optimized our mesenchymal stem cell (MSC) isolation

  10. Interleukin 17-producing γδT cells promote hepatic regeneration in mice.

    Rao, Raghavendra; Graffeo, Christopher S; Gulati, Rishabh; Jamal, Mohsin; Narayan, Suchithra; Zambirinis, Constantinos P; Barilla, Rocky; Deutsch, Michael; Greco, Stephanie H; Ochi, Atsuo; Tomkötter, Lena; Blobstein, Reuven; Avanzi, Antonina; Tippens, Daniel M; Gelbstein, Yisroel; Van Heerden, Eliza; Miller, George

    2014-08-01

    Subsets of leukocytes synergize with regenerative growth factors to promote hepatic regeneration. γδT cells are early responders to inflammation-induced injury in a number of contexts. We investigated the role of γδT cells in hepatic regeneration using mice with disruptions in Tcrd (encodes the T-cell receptor δ chain) and Clec7a (encodes C-type lectin domain family 7 member a, also known as DECTIN1). We performed partial hepatectomies on wild-type C57BL/6, CD45.1, Tcrd(-/-), or Clec7a(-/-) mice. Cells were isolated from livers of patients and mice via mechanical and enzymatic digestion. γδT cells were purified by fluorescence-activated cell sorting. In mice, partial hepatectomy up-regulated expression of CCL20 and ligands of Dectin-1, which was associated with recruitment and activation of γδT cells and their increased production of interleukin (IL)-17 family cytokines. Recruited γδT cells induced production of IL-6 by antigen-presenting cells and suppressed expression of interferon gamma by natural killer T cells, promoting hepatocyte proliferation. Absence of IL-17-producing γδT cells or deletion of Dectin-1 prevented development of regenerative phenotypes in subsets of innate immune cells. This slowed liver regeneration and was associated with reduced expression of regenerative growth factors and cell cycle regulators. Conversely, exogenous administration of IL-17 family cytokines or Dectin-1 ligands promoted regeneration. More broadly, we found that γδT cells are required for inflammatory responses mediated by IL-17 and Dectin-1. γδT cells regulate hepatic regeneration by producing IL-22 and IL-17, which have direct mitogenic effects on hepatocytes and promote a regenerative phenotype in hepatic leukocytes, respectively. Dectin-1 ligation is required for γδT cells to promote hepatic regeneration. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  11. Regenerating medicine related to the stem-cells and its mechanisms of action from adults cells

    Hernandez Ramirez, Porfirio

    2009-01-01

    Regenerating medicine is a branch of Medicine very developed in past years. Advances in this field have been closely linked with the new knowledge achieved on stem-cells and its ability to become in cells of different tissues. This type of medicine is based on the behaviors adopted by organism to substitute those damaged cells by the healthy ones by different processes in specific tissues. Therapeutic measures used may include the stem-cell transplantation, the use of soluble molecules, genic therapy and tissues engineering. Nowadays, the more used method is the adult stem-cells. However, is not well known the mechanisms by which the transplanted cells could to improve or to promote the tissue regeneration. To explain these mechanisms some hypotheses has been proposed including the cellular trans-differentiation, cells fusion, and the effects secondaries to cells release by cells of different soluble molecules with specific actions; in addition to the autocrine and paracrine effects that may have these soluble factors, it is suggested too the existence of a telecrine action. It is probable that more than one of these mechanisms be executed

  12. Lymphocyte development in irradiated thymuses: dynamics of colonization by progenitor cells and regeneration of resident cells

    Mehr, R.; Fridkis-Hareli, M.; Abel, L.; Segel, L.; Globerson, A.

    1995-01-01

    Lymphocyte development in irradiated thymuses was analyzed using two complementary strategies: an in vitro experimental model and computer simulations. In the in vitro model, fetal thymus lobes were irradiated and the regeneration of cells that survived irradiation were examined, with the results compared to those of reconstitution of the thymus by donor bone marrow cells and their competition with the thymic resident cells. In vitro measurements of resident cell kinetics showed that cell proliferation is slowed down significantly after a relatively low (10Gy) irradiation dose. Although the number of thymocytes that survived irradiation remained low for several days post-irradiation, further colonization by donor cells was not possible, unless performed within 6 h after irradiation. These experimental results, coupled with the analysis by computer simulations, suggest that bone marrow cell engraftment in the irradiated thymus may be limited by the presence of radiation-surviving thymic resident cells and the reduced availability of seeding niches. (Author)

  13. Modulating the stem cell niche for tissue regeneration

    Lane, Steven W; Williams, David A; Watt, Fiona M

    2015-01-01

    The field of regenerative medicine holds considerable promise for treating diseases that are currently intractable. Although many researchers are adopting the strategy of cell transplantation for tissue repair, an alternative approach to therapy is to manipulate the stem cell microenvironment, or niche, to facilitate repair by endogenous stem cells. The niche is highly dynamic, with multiple opportunities for intervention. These include administration of small molecules, biologics or biomaterials that target specific aspects of the niche, such as cell-cell and cell–extracellular matrix interactions, to stimulate expansion or differentiation of stem cells, or to cause reversion of differentiated cells to stem cells. Nevertheless, there are several challenges in targeting the niche therapeutically, not least that of achieving specificity of delivery and responses. We envisage that successful treatments in regenerative medicine will involve different combinations of factors to target stem cells and niche cells, applied at different times to effect recovery according to the dynamics of stem cell–niche interactions. PMID:25093887

  14. Skeletal muscle regeneration is modulated by inflammation

    Wenjun Yang

    2018-04-01

    Full Text Available Skeletal muscle regeneration is a complex process orchestrated by multiple steps. Recent findings indicate that inflammatory responses could play central roles in bridging initial muscle injury responses and timely muscle injury reparation. The various types of immune cells and cytokines have crucial roles in muscle regeneration process. In this review, we briefly summarise the functions of acute inflammation in muscle regeneration. The translational potential of this article: Immune system is closely relevant to the muscle regeneration. Understanding the mechanisms of inflammation in muscle regeneration is therefore critical for the development of effective regenerative, and therapeutic strategies in muscular disorders. This review provides information for muscle regeneration research regarding the effects of inflammation on muscle regeneration. Keywords: Chronic muscle disorders, Cytokines, Immune cells, Inflammation, Muscle regeneration, Muscle stem cells

  15. Genetically induced cell death in bulge stem cells reveals their redundancy for hair and epidermal regeneration.

    Driskell, Iwona; Oeztuerk-Winder, Feride; Humphreys, Peter; Frye, Michaela

    2015-03-01

    Adult mammalian epidermis contains multiple stem cell populations in which quiescent and more proliferative stem and progenitor populations coexist. However, the precise interrelation of these populations in homeostasis remains unclear. Here, we blocked the contribution of quiescent keratin 19 (K19)-expressing bulge stem cells to hair follicle formation through genetic ablation of the essential histone methyltransferase Setd8 that is required for the maintenance of adult skin. Deletion of Setd8 eliminated the contribution of bulge cells to hair follicle regeneration through inhibition of cell division and induction of cell death, but the growth and morphology of hair follicles were unaffected. Furthermore, ablation of Setd8 in the hair follicle bulge blocked the contribution of K19-postive stem cells to wounded epidermis, but the wound healing process was unaltered. Our data indicate that quiescent bulge stem cells are dispensable for hair follicle regeneration and epidermal injury in the short term and support the hypothesis that quiescent and cycling stem cell populations are equipotent. © 2014 AlphaMed Press.

  16. Skeletal Muscle Regeneration, Repair and Remodelling in Aging: The Importance of Muscle Stem Cells and Vascularization.

    Joanisse, Sophie; Nederveen, Joshua P; Snijders, Tim; McKay, Bryon R; Parise, Gianni

    2017-01-01

    Sarcopenia is the age-related loss of skeletal muscle mass and strength. Ultimately, sarcopenia results in the loss of independence, which imposes a large financial burden on healthcare systems worldwide. A critical facet of sarcopenia is the diminished ability for aged muscle to regenerate, repair and remodel. Over the years, research has focused on elucidating underlying mechanisms of sarcopenia and the impaired ability of muscle to respond to stimuli with aging. Muscle-specific stem cells, termed satellite cells (SC), play an important role in maintaining muscle health throughout the lifespan. It is well established that SC are essential in skeletal muscle regeneration, and it has been hypothesized that a reduction and/or dysregulation of the SC pool, may contribute to accelerated loss of skeletal muscle mass that is observed with advancing age. The preservation of skeletal muscle tissue and its ability to respond to stimuli may be impacted by reduced SC content and impaired function observed with aging. Aging is also associated with a reduction in capillarization of skeletal muscle. We have recently demonstrated that the distance between type II fibre-associated SC and capillaries is greater in older compared to younger adults. The greater distance between SC and capillaries in older adults may contribute to the dysregulation in SC activation ultimately impairing muscle's ability to remodel and, in extreme circumstances, regenerate. This viewpoint will highlight the importance of optimal SC activation in addition to skeletal muscle capillarization to maximize the regenerative potential of skeletal muscle in older adults. © 2016 S. Karger AG, Basel.

  17. Regulation of myogenesis and skeletal muscle regeneration: effects of oxygen levels on satellite cell activity.

    Chaillou, Thomas; Lanner, Johanna T

    2016-12-01

    Reduced oxygen (O 2 ) levels (hypoxia) are present during embryogenesis and exposure to altitude and in pathologic conditions. During embryogenesis, myogenic progenitor cells reside in a hypoxic microenvironment, which may regulate their activity. Satellite cells are myogenic progenitor cells localized in a local environment, suggesting that the O 2 level could affect their activity during muscle regeneration. In this review, we present the idea that O 2 levels regulate myogenesis and muscle regeneration, we elucidate the molecular mechanisms underlying myogenesis and muscle regeneration in hypoxia and depict therapeutic strategies using changes in O 2 levels to promote muscle regeneration. Severe hypoxia (≤1% O 2 ) appears detrimental for myogenic differentiation in vitro, whereas a 3-6% O 2 level could promote myogenesis. Hypoxia impairs the regenerative capacity of injured muscles. Although it remains to be explored, hypoxia may contribute to the muscle damage observed in patients with pathologies associated with hypoxia (chronic obstructive pulmonary disease, and peripheral arterial disease). Hypoxia affects satellite cell activity and myogenesis through mechanisms dependent and independent of hypoxia-inducible factor-1α. Finally, hyperbaric oxygen therapy and transplantation of hypoxia-conditioned myoblasts are beneficial procedures to enhance muscle regeneration in animals. These therapies may be clinically relevant to treatment of patients with severe muscle damage.-Chaillou, T. Lanner, J. T. Regulation of myogenesis and skeletal muscle regeneration: effects of oxygen levels on satellite cell activity. © FASEB.

  18. Mesenchymal Stem Cells as a Potent Cell Source for Bone Regeneration

    Elham Zomorodian

    2012-01-01

    Full Text Available While small bone defects heal spontaneously, large bone defects need surgical intervention for bone transplantation. Autologous bone grafts are the best and safest strategy for bone repair. An alternative method is to use allogenic bone graft. Both methods have limitations, particularly when bone defects are of a critical size. In these cases, bone constructs created by tissue engineering technologies are of utmost importance. Cells are one main component in the manufacture of bone construct. A few cell types, including embryonic stem cells (ESCs, adult osteoblast, and adult stem cells, can be used for this purpose. Mesenchymal stem cells (MSCs, as adult stem cells, possess characteristics that make them good candidate for bone repair. This paper discusses different aspects of MSCs that render them an appropriate cell type for clinical use to promote bone regeneration.

  19. The beneficial effect of genetically engineered Schwann cells with enhanced motility in peripheral nerve regeneration: review.

    Gravvanis, A I; Lavdas, A A; Papalois, A; Tsoutsos, D A; Matsas, R

    2007-01-01

    The importance of Schwann cells in promoting nerve regeneration across a conduit has been extensively reported in the literature, and Schwann cell motility has been acknowledged as a prerequisite for myelination of the peripheral nervous system during regeneration after injury. Review of recent literature and retrospective analysis of our studies with genetically modified Schwann Cells with increased motility in order to identify the underlying mechanism of action and outline the future trends in peripheral nerve repair. Schwann cell transduction with the pREV-retrovirus, for expression of Sialyl-Transferase-X, resulting in conferring Polysialyl-residues (PSA) on NCAM, increases their motility in-vitro and ensures nerve regeneration through silicone tubes after end-to-side neurorraphy in the rat sciatic nerve model, thus significantly promoting fiber maturation and functional outcome. An artificial nerve graft consisting of a type I collagen tube lined with the genetically modified Schwann cells with increased motility, used to bridge a defect in end-to-end fashion in the rat sciatic nerve model, was shown to promote nerve regeneration to a level equal to that of a nerve autograft. The use of genetically engineered Schwann cells with enhanced motility for grafting endoneural tubes promotes axonal regeneration, by virtue of the interaction of the transplanted cells with regenerating axonal growth cones as well as via the recruitment of endogenous Schwann cells. It is envisaged that mixed populations of Schwann cells, expressing PSA and one or more trophic factors, might further enhance the regenerating and remyelinating potential of the lesioned nerves.

  20. microRNA-183 is Essential for Hair Cell Regeneration after Neomycin Injury in Zebrafish.

    Kim, Chang Woo; Han, Ji Hyuk; Wu, Ling; Choi, Jae Young

    2018-01-01

    microRNAs (miRNAs) are non-coding RNAs composed of 20 to 22 nucleotides that regulate development and differentiation in various organs by silencing specific RNAs and regulating gene expression. In the present study, we show that the microRNA (miR)-183 cluster is upregulated during hair cell regeneration and that its inhibition reduces hair cell regeneration following neomycin-induced ototoxicity in zebrafish. miRNA expression patterns after neomycin exposure were analyzed using microarray chips. Quantitative polymerase chain reaction was performed to validate miR-183 cluster expression patterns following neomycin exposure (500 μM for 2 h). After injection of an antisense morpholino (MO) to miR-183 (MO-183) immediately after fertilization, hair cell regeneration after neomycin exposure in neuromast cells was evaluated by fluorescent staining (YO-PRO1). The MO-183 effect also was assessed in transgenic zebrafish larvae expressing green fluorescent protein (GFP) in inner ear hair cells. Microarray analysis clearly showed that the miR-183 cluster (miR-96, miR-182, and miR-183) was upregulated after neomycin treatment. We also confirmed upregulated expression of the miR-183 cluster during hair cell regeneration after neomycin-induced ototoxicity. miR-183 inhibition using MO-183 reduced hair cell regeneration in both wild-type and GFP transgenic zebrafish larvae. Our work demonstrates that the miR-183 cluster is essential for the regeneration of hair cells following ototoxic injury in zebrafish larvae. Therefore, regulation of the miR-183 cluster can be a novel target for stimulation of hair cell regeneration. © Copyright: Yonsei University College of Medicine 2018

  1. Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina.

    White, David T; Sengupta, Sumitra; Saxena, Meera T; Xu, Qingguo; Hanes, Justin; Ding, Ding; Ji, Hongkai; Mumm, Jeff S

    2017-05-02

    Müller glia (MG) function as inducible retinal stem cells in zebrafish, completely repairing the eye after damage. The innate immune system has recently been shown to promote tissue regeneration in which classic wound-healing responses predominate. However, regulatory roles for leukocytes during cellular regeneration-i.e., selective cell-loss paradigms akin to degenerative disease-are less well defined. To investigate possible roles innate immune cells play during retinal cell regeneration, we used intravital microscopy to visualize neutrophil, macrophage, and retinal microglia responses to induced rod photoreceptor apoptosis. Neutrophils displayed no reactivity to rod cell loss. Peripheral macrophage cells responded to rod cell loss, as evidenced by morphological transitions and increased migration, but did not enter the retina. Retinal microglia displayed multiple hallmarks of immune cell activation: increased migration, translocation to the photoreceptor cell layer, proliferation, and phagocytosis of dying cells. To test function during rod cell regeneration, we coablated microglia and rod cells or applied immune suppression and quantified the kinetics of ( i ) rod cell clearance, ( ii ) MG/progenitor cell proliferation, and ( iii ) rod cell replacement. Coablation and immune suppressants applied before cell loss caused delays in MG/progenitor proliferation rates and slowed the rate of rod cell replacement. Conversely, immune suppressants applied after cell loss had been initiated led to accelerated photoreceptor regeneration kinetics, possibly by promoting rapid resolution of an acute immune response. Our findings suggest that microglia control MG responsiveness to photoreceptor loss and support the development of immune-targeted therapeutic strategies for reversing cell loss associated with degenerative retinal conditions.

  2. Loss of niche-satellite cell interactions in syndecan-3 null mice alters muscle progenitor cell homeostasis improving muscle regeneration.

    Pisconti, Addolorata; Banks, Glen B; Babaeijandaghi, Farshad; Betta, Nicole Dalla; Rossi, Fabio M V; Chamberlain, Jeffrey S; Olwin, Bradley B

    2016-01-01

    The skeletal muscle stem cell niche provides an environment that maintains quiescent satellite cells, required for skeletal muscle homeostasis and regeneration. Syndecan-3, a transmembrane proteoglycan expressed in satellite cells, supports communication with the niche, providing cell interactions and signals to maintain quiescent satellite cells. Syndecan-3 ablation unexpectedly improves regeneration in repeatedly injured muscle and in dystrophic mice, accompanied by the persistence of sublaminar and interstitial, proliferating myoblasts. Additionally, muscle aging is improved in syndecan-3 null mice. Since syndecan-3 null myofiber-associated satellite cells downregulate Pax7 and migrate away from the niche more readily than wild type cells, syxndecan-3 appears to regulate satellite cell homeostasis and satellite cell homing to the niche. Manipulating syndecan-3 provides a promising target for development of therapies to enhance muscle regeneration in muscular dystrophies and in aged muscle.

  3. Original and regenerating lizard tail cartilage contain putative resident stem/progenitor cells.

    Alibardi, Lorenzo

    2015-11-01

    Regeneration of cartilaginous tissues is limited in mammals but it occurs with variable extension in lizards (reptiles), including in their vertebrae. The ability of lizard vertebrae to regenerate cartilaginous tissue that is later replaced with bone has been analyzed using tritiated thymidine autoradiography and 5BrdU immunocytochemistry after single pulse or prolonged-pulse and chase experiments. The massive cartilage regeneration that can restore broad vertebral regions and gives rise to a long cartilaginous tube in the regenerating tail, depends from the permanence of some chondrogenic cells within adult vertebrae. Few cells that retain tritiated thymidine or 5-bromodeoxy-uridine for over 35 days are mainly localized in the inter-vertebral cartilage and in sparse chondrogenic regions of the neural arch of the vertebrae, suggesting that they are putative resident stem/progenitor cells. The study supports previous hypothesis indicating that the massive regeneration of the cartilaginous tissue in damaged vertebrae and in the regenerating tail of lizards derive from resident stem cells mainly present in the cartilaginous areas of the vertebrae including in the perichondrium that are retained in adult lizards as growing centers for most of their lifetime. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Drosophila Sulf1 is required for the termination of intestinal stem cell division during regeneration.

    Takemura, Masahiko; Nakato, Hiroshi

    2017-01-15

    Stem cell division is activated to trigger regeneration in response to tissue damage. The molecular mechanisms by which this stem cell mitotic activity is properly repressed at the end of regeneration are poorly understood. Here, we show that a specific modification of heparan sulfate is crucial for regulating Drosophila intestinal stem cell (ISC) division during normal midgut homeostasis and regeneration. Loss of the extracellular heparan sulfate endosulfatase Sulf1 resulted in increased ISC division during normal homeostasis, which was caused by upregulation of mitogenic signaling including the JAK-STAT, EGFR and Hedgehog pathways. Using a regeneration model, we found that ISCs failed to properly halt division at the termination stage in Sulf1 mutants, showing that Sulf1 is required for terminating ISC division at the end of regeneration. We propose that post-transcriptional regulation of mitogen signaling by heparan sulfate structural modifications provides a new regulatory step for precise temporal control of stem cell activity during regeneration. © 2017. Published by The Company of Biologists Ltd.

  5. Cardiac tissue engineering and regeneration using cell-based therapy

    Alrefai MT

    2015-05-01

    Full Text Available Mohammad T Alrefai,1–3 Divya Murali,4 Arghya Paul,4 Khalid M Ridwan,1,2 John M Connell,1,2 Dominique Shum-Tim1,2 1Division of Cardiac Surgery, 2Division of Surgical Research, McGill University Health Center, Montreal, QC, Canada; 3King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia; 4Department of Chemical and Petroleum Engineering, School of Engineering, University of Kansas, Lawrence, KS, USA Abstract: Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells. Keywords: stem cells, cardiomyocytes, cardiac surgery, heart failure, myocardial ischemia, heart, scaffolds, organoids, cell sheet and tissue engineering

  6. Regeneration of musculoskeletal injuries using mesenchymal stem cells loaded scaffolds: review article

    Maryam Ataie

    2017-07-01

    Full Text Available An increase in the average age of the population and physical activities where the musculoskeletal system is involved as well as large number of people suffering from skeletal injuries which impose high costs on the society. Bone grafting is currently a standard clinical approach to treat or replace lost tissues. Autografts are the most common grafts, but they can lead to complications such as pain, infection, scarring and donor site morbidity. The alternative is allografts, but they also carry the risk of carrying infectious agents or immune rejection. Therefore, surgeons and researchers are looking for new therapeutic methods to improve bone tissue repair. The field of tissue engineering and the use of stem cells as an ideal cell source have emerged as a promising approach in recent years. Three main components in the field of tissue engineering include proper scaffolds, cells and growth factors that their combination leads to formation of tissue-engineered constructs, resulting in tissue repair and regeneration. The use of scaffolds with suitable properties could effectively improve the tissue function or even regenerate the damaged tissue. The main idea of tissue engineering is to design and fabricate an appropriate scaffold which can support cell attachment, proliferation, migration and differentiation to relevant tissue. Scaffold gives the tissue its structural and mechanical properties, for instance flexibility and stiffness that is related with the tissue functions. Biomaterials used to fabricate scaffolds can be categorized into natural or synthetic biodegradable or non-biodegradable materials. Polymers are the most widely used materials in tissue engineering. Growth factors are a group of proteins that cause cell proliferation and differentiation. Two main cell sources are specialized cells of desired tissue and stem cells. However, according to the low proliferation and limited accessibility to the cells of desired tissue, stem cells

  7. Divergent regeneration-competent cells adopt a common mechanism for callus initiation in angiosperms.

    Hu, Bo; Zhang, Guifang; Liu, Wu; Shi, Jianmin; Wang, Hua; Qi, Meifang; Li, Jiqin; Qin, Peng; Ruan, Ying; Huang, Hai; Zhang, Yijing; Xu, Lin

    2017-06-01

    In tissue culture, the formation of callus from detached explants is a key step in plant regeneration; however, the regenerative abilities in different species are variable. While nearly all parts of organs of the dicot Arabidopsis thaliana are ready for callus formation, mature regions of organs in monocot rice ( Oryza sativa ) and other cereals are extremely unresponsive to tissue culture. Whether there is a common molecular mechanism beyond these different regenerative phenomena is unclear. Here we show that the Arabidopsis and rice use different regeneration-competent cells to initiate callus, whereas the cells all adopt WUSCHEL-RELATED HOMEOBOX 11 ( WOX11 ) and WOX5 during cell fate transition. Different from Arabidopsis which maintains regeneration-competent cells in mature organs, rice exhausts those cells during organ maturation, resulting in regenerative inability in mature organs. Our study not only explains this old perplexity in agricultural biotechnology, but also provides common molecular markers for tissue culture of different angiosperm species.

  8. Catechins activate muscle stem cells by Myf5 induction and stimulate muscle regeneration.

    Kim, A Rum; Kim, Kyung Min; Byun, Mi Ran; Hwang, Jun-Ha; Park, Jung Il; Oh, Ho Taek; Kim, Hyo Kyeong; Jeong, Mi Gyeong; Hwang, Eun Sook; Hong, Jeong-Ho

    2017-07-22

    Muscle weakness is one of the most common symptoms in aged individuals and increases risk of mortality. Thus, maintenance of muscle mass is important for inhibiting aging. In this study, we investigated the effect of catechins, polyphenol compounds in green tea, on muscle regeneration. We found that (-)-epicatechin gallate (ECG) and (-)-epigallocatechin-3-gallate (EGCG) activate satellite cells by induction of Myf5 transcription factors. For satellite cell activation, Akt kinase was significantly induced after ECG treatment and ECG-induced satellite cell activation was blocked in the presence of Akt inhibitor. ECG also promotes myogenic differentiation through the induction of myogenic markers, including Myogenin and Muscle creatine kinase (MCK), in satellite and C2C12 myoblast cells. Finally, EGCG administration to mice significantly increased muscle fiber size for regeneration. Taken together, the results suggest that catechins stimulate muscle stem cell activation and differentiation for muscle regeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Dental-derived Stem Cells and whole Tooth Regeneration: an Overview

    Dannan, Aous

    2009-01-01

    The need for new dental tissue-replacement therapies is evident in recent reports which reveal startling statistics regarding the high incidence of tooth decay and tooth loss. Recent advances in the identification and characterization of dental stem cells, and in dental tissue-engineering strategies, suggest that bioengineering approaches may successfully be used to regenerate dental tissues and whole teeth. Interest in dental tissue-regeneration applications continues to increase as clinical...

  10. Transient HIF2A inhibition promotes satellite cell proliferation and muscle regeneration.

    Xie, Liwei; Yin, Amelia; Nichenko, Anna S; Beedle, Aaron M; Call, Jarrod A; Yin, Hang

    2018-03-13

    The remarkable regeneration capability of skeletal muscle depends on coordinated proliferation and differentiation of satellite cells. The self-renewal of satellite cells is critical for long-term maintenance of muscle regeneration potential. Hypoxia profoundly affects the proliferation, differentiation, and self-renewal of cultured myoblasts. However, the physiological relevance of hypoxia and hypoxia signaling in satellite cells in vivo remains largely unknown. Here, we report that satellite cells are in an intrinsic hypoxic state in vivo and express hypoxia-inducible factor 2A (HIF2A). HIF2A promotes the stemness and long-term homeostatic maintenance of satellite cells by maintaining the quiescence, increasing the self-renewal and blocking the myogenic differentiation of satellite cells. HIF2A stabilization in satellite cells cultured under normoxia augmented their engraftment potential in regenerative muscle. Reversely, HIF2A ablation led to the depletion of satellite cells and the consequent regenerative failure in the long-term. In contrast, transient pharmacological inhibition of HIF2A accelerated muscle regeneration by increasing satellite cell proliferation and differentiation. Mechanistically, HIF2A induces the quiescence/self-renewal of satellite cells by binding the promoter of Spry1 gene and activating Spry1 expression. These findings suggest that HIF2A is a pivotal mediator of hypoxia signaling in satellite cells and may be therapeutically targeted to improve muscle regeneration.

  11. Efficient gene knockin in axolotl and its use to test the role of satellite cells in limb regeneration.

    Fei, Ji-Feng; Schuez, Maritta; Knapp, Dunja; Taniguchi, Yuka; Drechsel, David N; Tanaka, Elly M

    2017-11-21

    Salamanders exhibit extensive regenerative capacities and serve as a unique model in regeneration research. However, due to the lack of targeted gene knockin approaches, it has been difficult to label and manipulate some of the cell populations that are crucial for understanding the mechanisms underlying regeneration. Here we have established highly efficient gene knockin approaches in the axolotl ( Ambystoma mexicanum ) based on the CRISPR/Cas9 technology. Using a homology-independent method, we successfully inserted both the Cherry reporter gene and a larger membrane-tagged Cherry-ER T2 -Cre-ER T2 (∼5-kb) cassette into axolotl Sox2 and Pax7 genomic loci. Depending on the size of the DNA fragments for integration, 5-15% of the F0 transgenic axolotl are positive for the transgene. Using these techniques, we have labeled and traced the PAX7-positive satellite cells as a major source contributing to myogenesis during axolotl limb regeneration. Our work brings a key genetic tool to molecular and cellular studies of axolotl regeneration.

  12. Enhancing pancreatic Beta-cell regeneration in vivo with pioglitazone and alogliptin.

    Hao Yin

    Full Text Available Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes.In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass.Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery.These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

  13. Analysis of cell performance and thermal regeneration of a lithium-tin cell having an immobilized fused-salt electrolyte

    Cairns, E. J.; Shimotake, H.

    1969-01-01

    Cell performance and thermal regeneration of a thermally regenerative cell uses lithium and tin and a fused-salt electrolyte. The emf of the Li-Sn cell, as a function of cathode-alloy composition, is shown to resemble that of the Na-Bi cell.

  14. Epithelial Regeneration After Gastric Ulceration Causes Prolonged Cell-Type AlterationsSummary

    Eitaro Aihara

    2016-09-01

    Full Text Available Background & Aims: The peptic ulcer heals through a complex process, although the ulcer relapse often occurs several years later after healing. Our hypothesis is that even after visual evidence of healing of gastric ulceration, the regenerated epithelium is aberrant for an extended interval, increasing susceptibility of the regenerated epithelium to damage and further diseases. Methods: Gastric ulcers were induced in mice by serosal topical application of acetic acid. Results: Gastric ulcers induced by acetic acid visually healed within 30 days. However, regenerated epithelial architecture was poor. The gene profile of regenerated tissue was abnormal, indicating increased stem/progenitor cells, deficient differentiated gastric cell types, and deranged cell homeostasis. Despite up-regulation of PDX1 in the regenerated epithelium, no mature antral cell type was observed. Four months after healing, the regenerated epithelium lacks parietal cells, trefoil factor 2 (TFF2 and (sex-determining region Y-box 9 (SOX9 remain up-regulated deep in the gastric gland, and the Na/H exchanger 2 (a TFF2 effector in gastric healing remains down-regulated. Gastric ulcer healing was strongly delayed in TFF2 knockout mice, and re-epithelialization was accompanied with mucous metaplasia. After Helicobacter pylori inoculum 30 days after ulceration, we observed that the gastric ulcer selectively relapses at the same site where it originally was induced. Follow-up evaluation at 8 months showed that the relapsed ulcer was not healed in H pylori–infected tissues. Conclusions: These findings show that this macroscopically regenerated epithelium has prolonged abnormal cell distribution and is differentially susceptible to subsequent damage by H pylori. Keywords: Gastric Ulcer Healing, Metaplasia, H pylori, SOX9, TFF2, NHE2

  15. PEDF-derived peptide promotes skeletal muscle regeneration through its mitogenic effect on muscle progenitor cells.

    Ho, Tsung-Chuan; Chiang, Yi-Pin; Chuang, Chih-Kuang; Chen, Show-Li; Hsieh, Jui-Wen; Lan, Yu-Wen; Tsao, Yeou-Ping

    2015-08-01

    In response injury, intrinsic repair mechanisms are activated in skeletal muscle to replace the damaged muscle fibers with new muscle fibers. The regeneration process starts with the proliferation of satellite cells to give rise to myoblasts, which subsequently differentiate terminally into myofibers. Here, we investigated the promotion effect of pigment epithelial-derived factor (PEDF) on muscle regeneration. We report that PEDF and a synthetic PEDF-derived short peptide (PSP; residues Ser(93)-Leu(112)) induce satellite cell proliferation in vitro and promote muscle regeneration in vivo. Extensively, soleus muscle necrosis was induced in rats by bupivacaine, and an injectable alginate gel was used to release the PSP in the injured muscle. PSP delivery was found to stimulate satellite cell proliferation in damaged muscle and enhance the growth of regenerating myofibers, with complete regeneration of normal muscle mass by 2 wk. In cell culture, PEDF/PSP stimulated C2C12 myoblast proliferation, together with a rise in cyclin D1 expression. PEDF induced the phosphorylation of ERK1/2, Akt, and STAT3 in C2C12 myoblasts. Blocking the activity of ERK, Akt, or STAT3 with pharmacological inhibitors attenuated the effects of PEDF/PSP on the induction of C2C12 cell proliferation and cyclin D1 expression. Moreover, 5-bromo-2'-deoxyuridine pulse-labeling demonstrated that PEDF/PSP stimulated primary rat satellite cell proliferation in myofibers in vitro. In summary, we report for the first time that PSP is capable of promoting the regeneration of skeletal muscle. The signaling mechanism involves the ERK, AKT, and STAT3 pathways. These results show the potential utility of this PEDF peptide for muscle regeneration. Copyright © 2015 the American Physiological Society.

  16. Making sense of Wnt signaling – linking hair cell regeneration to development

    Lina eJansson

    2015-03-01

    Full Text Available Wnt signaling is a highly conserved pathway crucial for development and homeostasis of multicellular organisms. Secreted Wnt ligands bind Frizzled receptors to regulate diverse processes such as axis patterning, cell division, and cell fate specification. They also serve to govern self-renewal of somatic stem cells in several adult tissues. The complexity of the pathway can be attributed to the myriad of Wnt and Frizzled combinations as well as its diverse context-dependent functions. In the developing mouse inner ear, Wnt signaling plays diverse roles, including specification of the otic placode and patterning of the otic vesicle. At later stages, its activity governs sensory hair cell specification, cell cycle regulation, and hair cell orientation. In regenerating sensory organs from non-mammalian species, Wnt signaling can also regulate the extent of proliferative hair cell regeneration. This review describes the current knowledge of the roles of Wnt signaling and Wnt-responsive cells in hair cell development and regeneration. We also discuss possible future directions and the potential application and limitation of Wnt signaling in augmenting hair cell regeneration.

  17. Mesenchymal Stem/Progenitor Cells Derived from Articular Cartilage, Synovial Membrane and Synovial Fluid for Cartilage Regeneration: Current Status and Future Perspectives.

    Huang, Yi-Zhou; Xie, Hui-Qi; Silini, Antonietta; Parolini, Ornella; Zhang, Yi; Deng, Li; Huang, Yong-Can

    2017-10-01

    Large articular cartilage defects remain an immense challenge in the field of regenerative medicine because of their poor intrinsic repair capacity. Currently, the available medical interventions can relieve clinical symptoms to some extent, but fail to repair the cartilaginous injuries with authentic hyaline cartilage. There has been a surge of interest in developing cell-based therapies, focused particularly on the use of mesenchymal stem/progenitor cells with or without scaffolds. Mesenchymal stem/progenitor cells are promising graft cells for tissue regeneration, but the most suitable source of cells for cartilage repair remains controversial. The tissue origin of mesenchymal stem/progenitor cells notably influences the biological properties and therapeutic potential. It is well known that mesenchymal stem/progenitor cells derived from synovial joint tissues exhibit superior chondrogenic ability compared with those derived from non-joint tissues; thus, these cell populations are considered ideal sources for cartilage regeneration. In addition to the progress in research and promising preclinical results, many important research questions must be answered before widespread success in cartilage regeneration is achieved. This review outlines the biology of stem/progenitor cells derived from the articular cartilage, the synovial membrane, and the synovial fluid, including their tissue distribution, function and biological characteristics. Furthermore, preclinical and clinical trials focusing on their applications for cartilage regeneration are summarized, and future research perspectives are discussed.

  18. Germ cell regeneration-mediated, enhanced mutagenesis in the ascidian Ciona intestinalis reveals flexible germ cell formation from different somatic cells.

    Yoshida, Keita; Hozumi, Akiko; Treen, Nicholas; Sakuma, Tetsushi; Yamamoto, Takashi; Shirae-Kurabayashi, Maki; Sasakura, Yasunori

    2017-03-15

    The ascidian Ciona intestinalis has a high regeneration capacity that enables the regeneration of artificially removed primordial germ cells (PGCs) from somatic cells. We utilized PGC regeneration to establish efficient methods of germ line mutagenesis with transcription activator-like effector nucleases (TALENs). When PGCs were artificially removed from animals in which a TALEN pair was expressed, somatic cells harboring mutations in the target gene were converted into germ cells, this germ cell population exhibited higher mutation rates than animals not subjected to PGC removal. PGC regeneration enables us to use TALEN expression vectors of specific somatic tissues for germ cell mutagenesis. Unexpectedly, cis elements for epidermis, neural tissue and muscle could be used for germ cell mutagenesis, indicating there are multiple sources of regenerated PGCs, suggesting a flexibility of differentiated Ciona somatic cells to regain totipotency. Sperm and eggs of a single hermaphroditic, PGC regenerated animal typically have different mutations, suggesting they arise from different cells. PGCs can be generated from somatic cells even though the maternal PGCs are not removed, suggesting that the PGC regeneration is not solely an artificial event but could have an endogenous function in Ciona. This study provides a technical innovation in the genome-editing methods, including easy establishment of mutant lines. Moreover, this study suggests cellular mechanisms and the potential evolutionary significance of PGC regeneration in Ciona. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Research on mass transfer and actual performance of the membrane regeneration air-conditioning system

    Li, Xiu-Wei; Zhang, Xiao-Song; Chen, Qing

    2015-01-01

    Highlights: • Experimental research has been made on the membrane air-conditioning system. • We develop mass transfer models for the membrane regeneration process. • The paper exposes the actual performance of the system. • Increase of membrane pairs improves the performance. - Abstract: Absorption air-conditioning system has great advantages in energy conservation and environmental protection. To improve the performance of the traditional system, the membrane regeneration absorption system was proposed. Its COP could approach 6 by regenerating absorbent solution with the ion exchange membranes. However, the theoretical conclusion has not been supported by the experiment. This paper presents the experimental research of the membrane regeneration process. It has investigated the mass transfer process, energy efficiency and actual performance under different working conditions. Based on that, a mass transfer model has been developed and the influences of some key parameters have been exposed. It found the regeneration performance is mainly influenced by the current intensity. The calculation results with the model agree well the experimental data. The actual efficiency was lower than 50%, caused by energy loss in heat and electrochemical reactions. The actual COP is between 1 and 3, lower current intensity and more membrane pairs could improve it.

  20. The effects of the stem cell on ciliary regeneration of injured rabbit sinonasal epithelium.

    Kavuzlu, Ali; Tatar, Emel Çadallı; Karagöz, Tuğba; Pınarlı, Ferda Alpaslan; Tatar, İlkan; Bayır, Ömer; Korkmaz, Mehmet Hakan

    2017-08-01

    Defects in mucosal healing after sinonasal surgery cause infection, scar formation causing obstruction, relapse of the disease within a shorter period and revision surgery. The present study aimed to create a functional ciliated epithelium using a stem cell and stem cell sheet of adipose tissue origin and to show such regeneration ultra-structurally on experimentally injured rabbit nasal epithelium. This was an experimental animal study and basic research. A total of 18 white New Zealand rabbits were divided into three groups. The medial wall of the maxillary sinus of the subjects was peeled off bilaterally. No additional procedure was applied to the subjects in Group 1. In Group 2, adipose tissue-derived mesenchymal stem cell was implanted on the wound edges of the subjects. In Group 3, a stem cell sheet of three layers was laid onto the defect area. All subjects were killed after 3 weeks. The presence of the stem cell stained with bromo-deoxyuridine was assessed with a light microscope, whereas cilia density, ciliated orientation and cilia structure were evaluated with a scanning electron microscope. Ciliary densities in Group 2 and Group 3 were statistically superior compared to the control group (p stem cell increased the healing of the injured maxillary sinus mucosa of the rabbits in terms of cilia presence, density and morphology regardless of the implementation technique. Level of evidence NA.

  1. Impact of NKT Cells and LFA-1 on Liver Regeneration under Subseptic Conditions.

    Ann-Kathrin Jörger

    Full Text Available Activation of the immune system in terms of subseptic conditions during liver regeneration is of paramount clinical importance. However, little is known about molecular mechanisms and their mediators that control hepatocyte proliferation. We sought to determine the functional role of immune cells, especially NKT cells, in response to partial hepatectomy (PH, and to uncover the impact of the integrin lymphocyte function-associated antigen-1 (LFA-1 on liver regeneration in a subseptic setting.Wild-type (WT and LFA-1-/- mice underwent a 2/3 PH and low-dose lipopolysaccharid (LPS application. Hepatocyte proliferation, immune cell infiltration, and cytokine profile in the liver parenchyma were determined.Low-dose LPS application after PH results in a significant delay of liver regeneration between 48h and 72h, which is associated with a reduced number of CD3+ cells within the regenerating liver. In absence of LFA-1, an impaired regenerative capacity was observed under low-dose LPS application. Analysis of different leukocyte subpopulations showed less CD3+NK1.1+ NKT cells in the liver parenchyma of LFA-1-/- mice after PH and LPS application compared to WT controls, while CD3-NK1.1+ NK cells markedly increased. Concordantly with this observation, lower levels of NKT cell related cytokines IL-12 and IL-23 were expressed in the regenerating liver of LFA-1-/- mice, while the expression of NK cell-associated CCL5 and IL-10 was increased compared to WT mice.A subseptic situation negatively alters hepatocyte proliferation. Within this scenario, we suggest an important impact of NKT cells and postulate a critical function for LFA-1 during processes of liver regeneration.

  2. Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration

    Jelnes, Peter; Santoni-Rugiu, Eric; Rasmussen, Morten

    2007-01-01

    The experimental protocols used in the investigation of stem cell-mediated liver regeneration in rodents are characterized by activation of the hepatic stem cell compartment in the canals of Hering followed by transit amplification of oval cells and their subsequent differentiation along hepatic...... the molecular phenotypes of oval cells in several of the most commonly used protocols of stem cell-mediated liver regeneration-namely, treatment with 2-acetylaminofluorene and partial (70%) hepatectomy (AAF/PHx); a choline-deficient, ethionine-supplemented (CDE) diet; a 3,5-diethoxycarbonyl-1,4-dihydro...... remarkable phenotypic discrepancies exhibited by oval cells in stem cell-mediated liver regeneration between rats and mice and underline the importance of careful extrapolation between individual species....

  3. Regenerating the injured kidney with human umbilical cord mesenchymal stem cell-derived exosomes

    Dorronsoro, Akaitz; Robbins, Paul D

    2013-01-01

    Transplantation of adult stem cells is being used to facilitate repair or regeneration of damaged or diseased tissues. However, in many cases, the therapeutic effects of the injected stem cells are mediated by factors secreted by stem cells and not by differentiation of the transplanted stem cells. Recent reports have identified a class of microvesicles, termed exosomes, released by stem cells that are able to confer therapeutic effects on injured renal and cardiac tissue. In this issue of St...

  4. Platelet-Rich Plasma Derived Growth Factors Contribute to Stem Cell Differentiation in Musculoskeletal Regeneration

    Yun Qian; Yun Qian; Qixin Han; Wei Chen; Wei Chen; Jialin Song; Jialin Song; Xiaotian Zhao; Yuanming Ouyang; Yuanming Ouyang; Weien Yuan; Cunyi Fan

    2017-01-01

    Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of differen...

  5. Growing Arabidopsis in vitro: cell suspensions, in vitro culture, and regeneration.

    Barkla, Bronwyn J; Vera-Estrella, Rosario; Pantoja, Omar

    2014-01-01

    An understanding of basic methods in Arabidopsis tissue culture is beneficial for any laboratory working on this model plant. Tissue culture refers to the aseptic growth of cells, organs, or plants in a controlled environment, in which physical, nutrient, and hormonal conditions can all be easily manipulated and monitored. The methodology facilitates the production of a large number of plants that are genetically identical over a relatively short growth period. Techniques, including callus production, cell suspension cultures, and plant regeneration, are all indispensable tools for the study of cellular biochemical and molecular processes. Plant regeneration is a key technology for successful stable plant transformation, while cell suspension cultures can be exploited for metabolite profiling and mining. In this chapter we report methods for the successful and highly efficient in vitro regeneration of plants and production of stable cell suspension lines from leaf explants of both Arabidopsis thaliana and Arabidopsis halleri.

  6. Lgr5 Identifies Progenitor Cells Capable of Taste Bud Regeneration after Injury.

    Norifumi Takeda

    Full Text Available Taste buds are composed of a variety of taste receptor cell types that develop from tongue epithelium and are regularly replenished under normal homeostatic conditions as well as after injury. The characteristics of cells that give rise to regenerating taste buds are poorly understood. Recent studies have suggested that Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5 identifies taste bud stem cells that contribute to homeostatic regeneration in adult circumvallate and foliate taste papillae, which are located in the posterior region of the tongue. Taste papillae in the adult anterior region of the tongue do not express Lgr5. Here, we confirm and extend these studies by demonstrating that Lgr5 cells give rise to both anterior and posterior taste buds during development, and are capable of regenerating posterior taste buds after injury induced by glossopharyngeal nerve transection.

  7. Lgr5 Identifies Progenitor Cells Capable of Taste Bud Regeneration after Injury.

    Takeda, Norifumi; Jain, Rajan; Li, Deqiang; Li, Li; Lu, Min Min; Epstein, Jonathan A

    2013-01-01

    Taste buds are composed of a variety of taste receptor cell types that develop from tongue epithelium and are regularly replenished under normal homeostatic conditions as well as after injury. The characteristics of cells that give rise to regenerating taste buds are poorly understood. Recent studies have suggested that Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) identifies taste bud stem cells that contribute to homeostatic regeneration in adult circumvallate and foliate taste papillae, which are located in the posterior region of the tongue. Taste papillae in the adult anterior region of the tongue do not express Lgr5. Here, we confirm and extend these studies by demonstrating that Lgr5 cells give rise to both anterior and posterior taste buds during development, and are capable of regenerating posterior taste buds after injury induced by glossopharyngeal nerve transection.

  8. Spinal cord regeneration in Xenopus tadpoles proceeds through activation of Sox2-positive cells

    2012-01-01

    Background In contrast to mammals, amphibians, such as adult urodeles (for example, newts) and anuran larvae (for example, Xenopus) can regenerate their spinal cord after injury. However, the cellular and molecular mechanisms involved in this process are still poorly understood. Results Here, we report that tail amputation results in a global increase of Sox2 levels and proliferation of Sox2+ cells. Overexpression of a dominant negative form of Sox2 diminished proliferation of spinal cord resident cells affecting tail regeneration after amputation, suggesting that spinal cord regeneration is crucial for the whole process. After spinal cord transection, Sox2+ cells are found in the ablation gap forming aggregates. Furthermore, Sox2 levels correlated with regenerative capabilities during metamorphosis, observing a decrease in Sox2 levels at non-regenerative stages. Conclusions Sox2+ cells contribute to the regeneration of spinal cord after tail amputation and transection. Sox2 levels decreases during metamorphosis concomitantly with the lost of regenerative capabilities. Our results lead to a working hypothesis in which spinal cord damage activates proliferation and/or migration of Sox2+ cells, thus allowing regeneration of the spinal cord after tail amputation or reconstitution of the ependymal epithelium after spinal cord transection. PMID:22537391

  9. Tissue-specific composite cell aggregates drive periodontium tissue regeneration by reconstructing a regenerative microenvironment.

    Zhu, Bin; Liu, Wenjia; Zhang, Hao; Zhao, Xicong; Duan, Yan; Li, Dehua; Jin, Yan

    2017-06-01

    Periodontitis is the most common cause of periodontium destruction. Regeneration of damaged tissue is the expected treatment goal. However, the regeneration of a functional periodontal ligament (PDL) insertion remains a difficulty, due to complicated factors. Recently, periodontal ligament stem cells (PDLSCs) and bone marrow-derived mesenchymal stem cells (BMMSCs) have been shown to participate in PDL regeneration, both pathologically and physiologically. Besides, interactions affect the biofunctions of different derived cells during the regenerative process. Therefore, the purpose of this study was to discuss the different derived composite cell aggregate (CA) systems of PDLSCs and BMMSCs (iliac-derived or jaw-derived) for periodontium regeneration under regenerative microenvironment reconstruction. Our results showed although all three mono-MSC CAs were compacted and the cells arranged regularly in them, jaw-derived BMMSC (JBMMSC) CAs secreted more extracellular matrix than the others. Furthermore, PDLSC/JBMMSC compound CAs highly expressed ALP, Col-I, fibronectin, integrin-β1 and periostin, suggesting that their biofunction is more appropriate for periodontal structure regeneration. Inspiringly, PDLSC/JBMMSC compound CAs regenerated more functional PDL-like tissue insertions in both nude mice ectopic and minipig orthotopic transplantation. The results indicated that the different derived CAs of PDLSCs/JBMMSCs provided an appropriate regenerative microenvironment facilitating a more stable and regular regeneration of functional periodontium tissue. This method may provide a possible strategy to solve periodontium defects in periodontitis and powerful experimental evidence for clinical applications in the future. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  10. Local myogenic pulp-derived cell injection enhances craniofacial muscle regeneration in vivo.

    Jung, J E; Song, M J; Shin, S; Choi, Y J; Kim, K H; Chung, C J

    2017-02-01

    To enhance myogenic differentiation in pulp cells isolated from extracted premolars by epigenetic modification using a DNA demethylation agent, 5-aza-2'-deoxycytidine (5-Aza), and to evaluate the potent stimulatory effect of 5-Aza-treated pulp cell injection for craniofacial muscle regeneration in vivo. Pulp cells were isolated from premolars extracted for orthodontic purposes from four adults (age range, 18-22.1 years). Levels of myogenic differentiation and functional contraction response in vitro were compared between pulp cells with or without pre-treatment of 5-Aza. Changes in muscle regeneration in response to green fluorescent protein (GFP)-labelled myogenic pulp cell injection in vivo were evaluated using a cardiotoxin (CTX)-induced muscle injury model of the gastrocnemius as well as the masseter muscle in mice. Pre-treatment of 5-Aza in pulp cells stimulated myotube formation, myogenic differentiation in terms of desmin and myogenin expression, and the level of collagen gel contraction. The local injection of 5-Aza pre-treated myogenic pulp cells was engrafted into the host tissue and indicated signs of enhanced muscle regeneration in both the gastrocnemius and the masseter muscles. The epigenetic modification of pulp cells from extracted premolars and the local injection of myogenic pulp cells may stimulate craniofacial muscles regeneration in vivo. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Regulation of Injury-Induced Ovarian Regeneration by Activation of Oogonial Stem Cells.

    Erler, Piril; Sweeney, Alexandra; Monaghan, James R

    2017-01-01

    Some animals have the ability to generate large numbers of oocytes throughout life. This raises the question whether persistent adult germline stem cell populations drive continuous oogenesis and whether they are capable of mounting a regenerative response after injury. Here we demonstrate the presence of adult oogonial stem cells (OSCs) in the adult axolotl salamander ovary and show that ovarian injury induces OSC activation and functional regeneration of the ovaries to reproductive capability. Cells that have morphological similarities to germ cells were identified in the developing and adult ovaries via histological analysis. Genes involved in germ cell maintenance including Vasa, Oct4, Sox2, Nanog, Bmp15, Piwil1, Piwil2, Dazl, and Lhx8 were expressed in the presumptive OSCs. Colocalization of Vasa protein with H3 mitotic marker showed that both oogonial and spermatogonial adult stem cells were mitotically active. Providing evidence of stemness and viability of adult OSCs, enhanced green fluorescent protein (EGFP) adult OSCs grafted into white juvenile host gonads gave rise to EGFP OSCs, and oocytes. Last, the axolotl ovaries completely regenerated after partial ovariectomy injury. During regeneration, OSC activation resulted in rapid differentiation into new oocytes, which was demonstrated by Vasa + /BrdU + coexpression. Furthermore, follicle cell proliferation promoted follicle maturation during ovarian regeneration. Overall, these results show that adult oogenesis occurs via proliferation of endogenous OSCs in a tetrapod and mediates ovarian regeneration. This study lays the foundations to elucidate mechanisms of ovarian regeneration that will assist regenerative medicine in treating premature ovarian failure and reduced fertility. Stem Cells 2017;35:236-247. © 2016 AlphaMed Press.

  12. Pre-transplantation specification of stem cells to cardiac lineage for regeneration of cardiac tissue.

    Mayorga, Maritza; Finan, Amanda; Penn, Marc

    2009-03-01

    Myocardial infarction (MI) is a lead cause of mortality in the Western world. Treatment of acute MI is focused on restoration of antegrade flow which inhibits further tissue loss, but does not restore function to damaged tissue. Chronic therapy for injured myocardial tissue involves medical therapy that attempts to minimize pathologic remodeling of the heart. End stage therapy for chronic heart failure (CHF) involves inotropic therapy to increase surviving cardiac myocyte function or mechanical augmentation of cardiac performance. Not until the point of heart transplantation, a limited resource at best, does therapy focus on the fundamental problem of needing to replace injured tissue with new contractile tissue. In this setting, the potential for stem cell therapy has garnered significant interest for its potential to regenerate or create new contractile cardiac tissue. While to date adult stem cell therapy in clinical trials has suggested potential benefit, there is waning belief that the approaches used to date lead to regeneration of cardiac tissue. As the literature has better defined the pathways involved in cardiac differentiation, preclinical studies have suggested that stem cell pretreatment to direct stem cell differentiation prior to stem cell transplantation may be a more efficacious strategy for inducing cardiac regeneration. Here we review the available literature on pre-transplantation conditioning of stem cells in an attempt to better understand stem cell behavior and their readiness in cell-based therapy for myocardial regeneration.

  13. Bone marrow adipocytes promote the regeneration of stem cells and hematopoiesis by secreting SCF

    Zhou, Bo O.; Yu, Hua; Yue, Rui; Zhao, Zhiyu; Rios, Jonathan J.; Naveiras, Olaia; Morrison, Sean J.

    2017-01-01

    Endothelial cells and Leptin Receptor+ (LepR+) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including Stem Cell Factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER+ progenitors, which represent ~5% of LepR+ cells, and proliferate after irradiation. Scf deletion using Adipoq-Cre/ER inhibited hematopoietic regeneration after irradiation or 5-fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR+ cells, but not endothelial, hematopoietic, or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq-Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 ‘fatless” mice exhibited delayed hematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes hematopoietic regeneration. PMID:28714970

  14. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF.

    Zhou, Bo O; Yu, Hua; Yue, Rui; Zhao, Zhiyu; Rios, Jonathan J; Naveiras, Olaia; Morrison, Sean J

    2017-08-01

    Endothelial cells and leptin receptor + (LepR + ) stromal cells are critical sources of haematopoietic stem cell (HSC) niche factors, including stem cell factor (SCF), in bone marrow. After irradiation or chemotherapy, these cells are depleted while adipocytes become abundant. We discovered that bone marrow adipocytes synthesize SCF. They arise from Adipoq-Cre/ER + progenitors, which represent ∼5% of LepR + cells, and proliferate after irradiation. Scf deletion using Adipoq-Cre/ER inhibited haematopoietic regeneration after irradiation or 5-fluorouracil treatment, depleting HSCs and reducing mouse survival. Scf from LepR + cells, but not endothelial, haematopoietic or osteoblastic cells, also promoted regeneration. In non-irradiated mice, Scf deletion using Adipoq-Cre/ER did not affect HSC frequency in long bones, which have few adipocytes, but depleted HSCs in tail vertebrae, which have abundant adipocytes. A-ZIP/F1 'fatless' mice exhibited delayed haematopoietic regeneration in long bones but not in tail vertebrae, where adipocytes inhibited vascularization. Adipocytes are a niche component that promotes haematopoietic regeneration.

  15. MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration

    Mokalled, Mayssa H.; Johnson, Aaron N.; Creemers, Esther E.; Olson, Eric N.

    2012-01-01

    In response to skeletal muscle injury, satellite cells, which function as a myogenic stem cell population, become activated, expand through proliferation, and ultimately fuse with each other and with damaged myofibers to promote muscle regeneration. Here, we show that members of the Myocardin family

  16. The Role of Genetically Modified Mesenchymal Stem Cells in Urinary Bladder Regeneration.

    Devon C Snow-Lisy

    Full Text Available Recent studies have demonstrated that mesenchymal stem cells (MSCs combined with CD34+ hematopoietic/stem progenitor cells (HSPCs can function as surrogate urinary bladder cells to synergistically promote multi-faceted bladder tissue regeneration. However, the molecular pathways governing these events are unknown. The pleiotropic effects of Wnt5a and Cyr61 are known to affect aspects of hematopoiesis, angiogenesis, and muscle and nerve regeneration. Within this study, the effects of Cyr61 and Wnt5a on bladder tissue regeneration were evaluated by grafting scaffolds containing modified human bone marrow derived MSCs. These cell lines were engineered to independently over-express Wnt5a or Cyr61, or to exhibit reduced expression of Cyr61 within the context of a nude rat bladder augmentation model. At 4 weeks post-surgery, data demonstrated increased vessel number (~250 vs ~109 vessels/mm2 and bladder smooth muscle content (~42% vs ~36% in Cyr61OX (over-expressing vs Cyr61KD (knock-down groups. Muscle content decreased to ~25% at 10 weeks in Cyr61KD groups. Wnt5aOX resulted in high numbers of vessels and muscle content (~206 vessels/mm2 and ~51%, respectively at 4 weeks. Over-expressing cell constructs resulted in peripheral nerve regeneration while Cyr61KD animals were devoid of peripheral nerve regeneration at 4 weeks. At 10 weeks post-grafting, peripheral nerve regeneration was at a minimal level for both Cyr61OX and Wnt5aOX cell lines. Blood vessel and bladder functionality were evident at both time-points in all animals. Results from this study indicate that MSC-based Cyr61OX and Wnt5aOX cell lines play pivotal roles with regards to increasing the levels of functional vasculature, influencing muscle regeneration, and the regeneration of peripheral nerves in a model of bladder augmentation. Wnt5aOX constructs closely approximated the outcomes previously observed with the co-transplantation of MSCs with CD34+ HSPCs and may be specifically

  17. The Role of Genetically Modified Mesenchymal Stem Cells in Urinary Bladder Regeneration.

    Snow-Lisy, Devon C; Diaz, Edward C; Bury, Matthew I; Fuller, Natalie J; Hannick, Jessica H; Ahmad, Nida; Sharma, Arun K

    2015-01-01

    Recent studies have demonstrated that mesenchymal stem cells (MSCs) combined with CD34+ hematopoietic/stem progenitor cells (HSPCs) can function as surrogate urinary bladder cells to synergistically promote multi-faceted bladder tissue regeneration. However, the molecular pathways governing these events are unknown. The pleiotropic effects of Wnt5a and Cyr61 are known to affect aspects of hematopoiesis, angiogenesis, and muscle and nerve regeneration. Within this study, the effects of Cyr61 and Wnt5a on bladder tissue regeneration were evaluated by grafting scaffolds containing modified human bone marrow derived MSCs. These cell lines were engineered to independently over-express Wnt5a or Cyr61, or to exhibit reduced expression of Cyr61 within the context of a nude rat bladder augmentation model. At 4 weeks post-surgery, data demonstrated increased vessel number (~250 vs ~109 vessels/mm2) and bladder smooth muscle content (~42% vs ~36%) in Cyr61OX (over-expressing) vs Cyr61KD (knock-down) groups. Muscle content decreased to ~25% at 10 weeks in Cyr61KD groups. Wnt5aOX resulted in high numbers of vessels and muscle content (~206 vessels/mm2 and ~51%, respectively) at 4 weeks. Over-expressing cell constructs resulted in peripheral nerve regeneration while Cyr61KD animals were devoid of peripheral nerve regeneration at 4 weeks. At 10 weeks post-grafting, peripheral nerve regeneration was at a minimal level for both Cyr61OX and Wnt5aOX cell lines. Blood vessel and bladder functionality were evident at both time-points in all animals. Results from this study indicate that MSC-based Cyr61OX and Wnt5aOX cell lines play pivotal roles with regards to increasing the levels of functional vasculature, influencing muscle regeneration, and the regeneration of peripheral nerves in a model of bladder augmentation. Wnt5aOX constructs closely approximated the outcomes previously observed with the co-transplantation of MSCs with CD34+ HSPCs and may be specifically targeted as an

  18. Recent Advancements in the Regeneration of Auditory Hair Cells and Hearing Restoration

    Rahul Mittal

    2017-07-01

    Full Text Available Neurosensory responses of hearing and balance are mediated by receptors in specialized neuroepithelial sensory cells. Any disruption of the biochemical and molecular pathways that facilitate these responses can result in severe deficits, including hearing loss and vestibular dysfunction. Hearing is affected by both environmental and genetic factors, with impairment of auditory function being the most common neurosensory disorder affecting 1 in 500 newborns, as well as having an impact on the majority of elderly population. Damage to auditory sensory cells is not reversible, and if sufficient damage and cell death have taken place, the resultant deficit may lead to permanent deafness. Cochlear implants are considered to be one of the most successful and consistent treatments for deaf patients, but only offer limited recovery at the expense of loss of residual hearing. Recently there has been an increased interest in the auditory research community to explore the regeneration of mammalian auditory hair cells and restoration of their function. In this review article, we examine a variety of recent therapies, including genetic, stem cell and molecular therapies as well as discussing progress being made in genome editing strategies as applied to the restoration of hearing function.

  19. Novel application of stem cell-derived factors for periodontal regeneration

    Inukai, Takeharu, E-mail: t-inukai@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Katagiri, Wataru, E-mail: w-kat@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Yoshimi, Ryoko, E-mail: lianzi@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Osugi, Masashi, E-mail: masashi@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Kawai, Takamasa, E-mail: takamasa@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Hibi, Hideharu, E-mail: hibihi@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan); Ueda, Minoru, E-mail: mueda@med.nagoya-u.ac.jp [Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine (Japan)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer Mesenchymal stem cells (MSCs) secrete a variety of cytokines. Black-Right-Pointing-Pointer Cytokines were detected in conditioned medium from cultured MSCs (MSC-CM). Black-Right-Pointing-Pointer MSC-CM enhanced activation of dog MSCs and periodontal ligament cells. Black-Right-Pointing-Pointer MSC-CM significantly promoted alveolar bone and cementum regeneration. Black-Right-Pointing-Pointer Multiple cytokines contained in MSC-CM promote periodontal regeneration. -- Abstract: The effect of conditioned medium from cultured mesenchymal stem cells (MSC-CM) on periodontal regeneration was evaluated. In vitro, MSC-CM stimulated migration and proliferation of dog MSCs (dMSCs) and dog periodontal ligament cells (dPDLCs). Cytokines such as insulin-like growth factor, vascular endothelial growth factor, transforming growth factor-{beta}1, and hepatocyte growth factor were detected in MSC-CM. In vivo, one-wall critical-size, intrabony periodontal defects were surgically created in the mandible of dogs. Dogs with these defects were divided into three groups that received MSC-CM, PBS, or no implants. Absorbable atelo-collagen sponges (TERUPLUG Registered-Sign ) were used as a scaffold material. Based on radiographic and histological observation 4 weeks after transplantation, the defect sites in the MSC-CM group displayed significantly greater alveolar bone and cementum regeneration than the other groups. These findings suggest that MSC-CM enhanced periodontal regeneration due to multiple cytokines contained in MSC-CM.

  20. PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis.

    Kim, Moon Jong; Xia, Bo; Suh, Han Na; Lee, Sung Ho; Jun, Sohee; Lien, Esther M; Zhang, Jie; Chen, Kaifu; Park, Jae-Il

    2018-03-12

    The underlying mechanisms of how self-renewing cells are controlled in regenerating tissues and cancer remain ambiguous. PCNA-associated factor (PAF) modulates DNA repair via PCNA. Also, PAF hyperactivates Wnt/β-catenin signaling independently of PCNA interaction. We found that PAF is expressed in intestinal stem and progenitor cells (ISCs and IPCs) and markedly upregulated during intestinal regeneration and tumorigenesis. Whereas PAF is dispensable for intestinal homeostasis, upon radiation injury, genetic ablation of PAF impairs intestinal regeneration along with the severe loss of ISCs and Myc expression. Mechanistically, PAF conditionally occupies and transactivates the c-Myc promoter, which induces the expansion of ISCs/IPCs during intestinal regeneration. In mouse models, PAF knockout inhibits Apc inactivation-driven intestinal tumorigenesis with reduced tumor cell stemness and suppressed Wnt/β-catenin signaling activity, supported by transcriptome profiling. Collectively, our results unveil that the PAF-Myc signaling axis is indispensable for intestinal regeneration and tumorigenesis by positively regulating self-renewing cells. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Novel application of stem cell-derived factors for periodontal regeneration

    Inukai, Takeharu; Katagiri, Wataru; Yoshimi, Ryoko; Osugi, Masashi; Kawai, Takamasa; Hibi, Hideharu; Ueda, Minoru

    2013-01-01

    Highlights: ► Mesenchymal stem cells (MSCs) secrete a variety of cytokines. ► Cytokines were detected in conditioned medium from cultured MSCs (MSC-CM). ► MSC-CM enhanced activation of dog MSCs and periodontal ligament cells. ► MSC-CM significantly promoted alveolar bone and cementum regeneration. ► Multiple cytokines contained in MSC-CM promote periodontal regeneration. -- Abstract: The effect of conditioned medium from cultured mesenchymal stem cells (MSC-CM) on periodontal regeneration was evaluated. In vitro, MSC-CM stimulated migration and proliferation of dog MSCs (dMSCs) and dog periodontal ligament cells (dPDLCs). Cytokines such as insulin-like growth factor, vascular endothelial growth factor, transforming growth factor-β1, and hepatocyte growth factor were detected in MSC-CM. In vivo, one-wall critical-size, intrabony periodontal defects were surgically created in the mandible of dogs. Dogs with these defects were divided into three groups that received MSC-CM, PBS, or no implants. Absorbable atelo-collagen sponges (TERUPLUG®) were used as a scaffold material. Based on radiographic and histological observation 4 weeks after transplantation, the defect sites in the MSC-CM group displayed significantly greater alveolar bone and cementum regeneration than the other groups. These findings suggest that MSC-CM enhanced periodontal regeneration due to multiple cytokines contained in MSC-CM.

  2. Analysis of Cell Proliferation in Newt (Pleurodeles waltl) Tissue Regeneration during Spaceflight in Foton M-2

    Almeida, E. A. C.; Roden, C.; Phillips, J. A.; Yusuf, R.; Globus, R. K.; Searby, N.; Vercoutere, W.; Morey-Holton, E.; Tairbekov, M.; Grigoryan, N.; hide

    2006-01-01

    Terrestrial organisms exposed to microgravity during spaceflight expe rience musculoskeletal degeneration. It is still not understood if lo nger-term exposures to microgravity induce degeneration in other tiss ues, and if these effects are also observed in neutrally buoyant aqu atic organisms that may be pre-adapted to mechanical unloading. The " Regeneration" experiment conducted collaboratively between Russian an d US scientists for 16 days in the Russian Foton M-2 spaceflight soug ht to test the hypothesis that microgravity alters the proliferation of cells in regenerating tail tissue of the newt Pleurodeles waltl. Our initial results indicate that we successfUlly delivered the proli feration marker 5-bromo-2'-deoxy Uridine (BrdU) during spaceflight, and that it was incorporated in the nuclei of cells in regenerating tis sues. Cells in spaceflight tail regenerates proliferated at a slight ly slower rate and were more undifferentiated than those in ground sy nchronous controls. In addition, the size of regenerating tails from spaceflight was smaller than synchronous controls. However, onboard temperature recordings show that the temperature in spaceflight was a bout 2 C lower than ground synchronous controls, possibly explaining the observed differences. Additional post-facto ground controls at ma tched temperatures will correctly determine the effects of spaceflig ht on regenerative cell proliferation in the newt.

  3. Hair cell regeneration in sensory epithelia from the inner ear of a urodele amphibian.

    Taylor, Ruth R; Forge, Andrew

    2005-03-28

    The capacity of urodele amphibians to regenerate a variety of body parts is providing insight into mechanisms of tissue regeneration in vertebrates. In this study the ability of the newt, Notophthalmus viridescens, to regenerate inner ear hair cells in vitro was examined. Intact otic capsules were maintained in organotypic culture. Incubation in 2 mM gentamicin for 48 hours resulted in ablation of all hair cells from the saccular maculae. Thus, any hair cell recovery was not due to repair of damaged hair cells. Immature hair cells were subsequently observed at approximately 12 days posttreatment. Their number increased over the following 7-14 days to reach approximately 30% of the normal number. Following incubation of damaged tissue with bromodeoxyuridine (BrdU), labeled nuclei were confined strictly within regions of hair cell loss, indicating that supporting cells entered S-phase. Double labeling of tissue with two different hair cell markers and three different antibodies to BrdU in various combinations, however, all showed that the nuclei of cells that labeled with hair cell markers did not label for BrdU. This suggested that the new hair cells were not derived from those cells that had undergone mitosis. When mitosis was blocked with aphidicolin, new hair cells were still generated. The results suggest that direct phenotypic conversion of supporting cells into hair cells without an intervening mitotic event is a major mechanism of hair cell regeneration in the newt. A similar mechanism has been proposed for the hair cell recovery phenomenon observed in the vestibular organs of mammals. Copyright 2005 Wiley-Liss, Inc.

  4. Retinoic Acid Signaling Mediates Hair Cell Regeneration by Repressing p27kip and sox2 in Supporting Cells.

    Rubbini, Davide; Robert-Moreno, Àlex; Hoijman, Esteban; Alsina, Berta

    2015-11-25

    During development, otic sensory progenitors give rise to hair cells and supporting cells. In mammalian adults, differentiated and quiescent sensory cells are unable to generate new hair cells when these are lost due to various insults, leading to irreversible hearing loss. Retinoic acid (RA) has strong regenerative capacity in several organs, but its role in hair cell regeneration is unknown. Here, we use genetic and pharmacological inhibition to show that the RA pathway is required for hair cell regeneration in zebrafish. When regeneration is induced by laser ablation in the inner ear or by neomycin treatment in the lateral line, we observe rapid activation of several components of the RA pathway, with dynamics that position RA signaling upstream of other signaling pathways. We demonstrate that blockade of the RA pathway impairs cell proliferation of supporting cells in the inner ear and lateral line. Moreover, in neuromast, RA pathway regulates the transcription of p27(kip) and sox2 in supporting cells but not fgf3. Finally, genetic cell-lineage tracing using Kaede photoconversion demonstrates that de novo hair cells derive from FGF-active supporting cells. Our findings reveal that RA has a pivotal role in zebrafish hair cell regeneration by inducing supporting cell proliferation, and shed light on the underlying transcriptional mechanisms involved. This signaling pathway might be a promising approach for hearing recovery. Hair cells are the specialized mechanosensory cells of the inner ear that capture auditory and balance sensory input. Hair cells die after acoustic trauma, ototoxic drugs or aging diseases, leading to progressive hearing loss. Mammals, in contrast to zebrafish, lack the ability to regenerate hair cells. Here, we find that retinoic acid (RA) pathway is required for hair cell regeneration in vivo in the zebrafish inner ear and lateral line. RA pathway is activated very early upon hair cell loss, promotes cell proliferation of progenitor cells

  5. Platelet-Rich Plasma Derived Growth Factors Contribute to Stem Cell Differentiation in Musculoskeletal Regeneration

    Yun Qian

    2017-10-01

    Full Text Available Stem cell treatment and platelet-rich plasma (PRP therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of PRP derived GFs with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration.

  6. Platelet-rich plasma derived growth factors contribute to stem cell differentiation in musculoskeletal regeneration

    Qian, Yun; Han, Qixin; Chen, Wei; Song, Jialin; Zhao, Xiaotian; Ouyang, Yuanming; Yuan, Weien; Fan, Cunyi

    2017-10-01

    Stem cell treatment and platelet-rich plasma (PRP) therapy are two significant issues in regenerative medicine. Stem cells such as bone marrow mesenchymal stem cells, adipose-derived stem cells and periodontal ligament stem cells can be successfully applied in the field of tissue regeneration. PRP, a natural product isolated from whole blood, can secrete multiple growth factors (GFs) for regulating physiological activities. These GFs can stimulate proliferation and differentiation of different stem cells in injury models. Therefore, combination of both agents receives wide expectations in regenerative medicine, especially in bone, cartilage and tendon repair. In this review, we thoroughly discussed the interaction and underlying mechanisms of platelet-rich plasma derived growth factors with stem cells, and assessed their functions in cell differentiation for musculoskeletal regeneration.

  7. 3D Printing of Lotus Root-Like Biomimetic Materials for Cell Delivery and Tissue Regeneration.

    Feng, Chun; Zhang, Wenjie; Deng, Cuijun; Li, Guanglong; Chang, Jiang; Zhang, Zhiyuan; Jiang, Xinquan; Wu, Chengtie

    2017-12-01

    Biomimetic materials have drawn more and more attention in recent years. Regeneration of large bone defects is still a major clinical challenge. In addition, vascularization plays an important role in the process of large bone regeneration and microchannel structure can induce endothelial cells to form rudimentary vasculature. In recent years, 3D printing scaffolds are major materials for large bone defect repair. However, these traditional 3D scaffolds have low porosity and nonchannel structure, which impede angiogenesis and osteogenesis. In this study, inspired by the microstructure of natural plant lotus root, biomimetic materials with lotus root-like structures are successfully prepared via a modified 3D printing strategy. Compared with traditional 3D materials, these biomimetic materials can significantly improve in vitro cell attachment and proliferation as well as promote in vivo osteogenesis, indicating potential application for cell delivery and bone regeneration.

  8. 3D Printing of Lotus Root‐Like Biomimetic Materials for Cell Delivery and Tissue Regeneration

    Feng, Chun; Zhang, Wenjie; Deng, Cuijun; Li, Guanglong; Chang, Jiang; Zhang, Zhiyuan

    2017-01-01

    Abstract Biomimetic materials have drawn more and more attention in recent years. Regeneration of large bone defects is still a major clinical challenge. In addition, vascularization plays an important role in the process of large bone regeneration and microchannel structure can induce endothelial cells to form rudimentary vasculature. In recent years, 3D printing scaffolds are major materials for large bone defect repair. However, these traditional 3D scaffolds have low porosity and nonchannel structure, which impede angiogenesis and osteogenesis. In this study, inspired by the microstructure of natural plant lotus root, biomimetic materials with lotus root‐like structures are successfully prepared via a modified 3D printing strategy. Compared with traditional 3D materials, these biomimetic materials can significantly improve in vitro cell attachment and proliferation as well as promote in vivo osteogenesis, indicating potential application for cell delivery and bone regeneration. PMID:29270348

  9. Radiation effects on regeneration and T-cell-inducing function of the thymus

    Hirokawa, K.; Sado, T.

    1984-01-01

    Radiation effects on regeneration and T-cell-inducing function of the thymus were studied in three sets of experiments. When TXB mice were grafted with 1-week-old thymus which had been previously irradiated at various doses, an exponential decrease was observed in the morphological regeneration of the thymus grafts and in their T-cell-inducing function at doses of 600 R and over, showing about 10% that of the control at 1500 R. When in situ thymus of adult mice was locally irradiated, the radiation effect on T-cell-inducing function was less pronounced as compared with the first experiment; i.e., about 40% of the control at 1797 R. When in situ thymus of 1-day-old newborn mice was locally irradiated, regeneration potential of 1-day-old newborn thymus was highly resistant to radiation exposure and no effect on immunological functions was observed even by local irradiation of 2000 R

  10. Stem Cell Technology in Cardiac Regeneration: A Pluripotent Stem Cell Promise.

    Duelen, Robin; Sampaolesi, Maurilio

    2017-02-01

    Despite advances in cardiovascular biology and medical therapy, heart disorders are the leading cause of death worldwide. Cell-based regenerative therapies become a promising treatment for patients affected by heart failure, but also underline the need for reproducible results in preclinical and clinical studies for safety and efficacy. Enthusiasm has been tempered by poor engraftment, survival and differentiation of the injected adult stem cells. The crucial challenge is identification and selection of the most suitable stem cell type for cardiac regenerative medicine. Human pluripotent stem cells (PSCs) have emerged as attractive cell source to obtain cardiomyocytes (CMs), with potential applications, including drug discovery and toxicity screening, disease modelling and innovative cell therapies. Lessons from embryology offered important insights into the development of stem cell-derived CMs. However, the generation of a CM population, uniform in cardiac subtype, adult maturation and functional properties, is highly recommended. Moreover, hurdles regarding tumorigenesis, graft cell death, immune rejection and arrhythmogenesis need to be overcome in clinical practice. Here we highlight the recent progression in PSC technologies for the regeneration of injured heart. We review novel strategies that might overcome current obstacles in heart regenerative medicine, aiming at improving cell survival and functional integration after cell transplantation. Copyright © 2017. Published by Elsevier B.V.

  11. Stem Cell Technology in Cardiac Regeneration: A Pluripotent Stem Cell Promise

    Robin Duelen

    2017-02-01

    Full Text Available Despite advances in cardiovascular biology and medical therapy, heart disorders are the leading cause of death worldwide. Cell-based regenerative therapies become a promising treatment for patients affected by heart failure, but also underline the need for reproducible results in preclinical and clinical studies for safety and efficacy. Enthusiasm has been tempered by poor engraftment, survival and differentiation of the injected adult stem cells. The crucial challenge is identification and selection of the most suitable stem cell type for cardiac regenerative medicine. Human pluripotent stem cells (PSCs have emerged as attractive cell source to obtain cardiomyocytes (CMs, with potential applications, including drug discovery and toxicity screening, disease modelling and innovative cell therapies. Lessons from embryology offered important insights into the development of stem cell-derived CMs. However, the generation of a CM population, uniform in cardiac subtype, adult maturation and functional properties, is highly recommended. Moreover, hurdles regarding tumorigenesis, graft cell death, immune rejection and arrhythmogenesis need to be overcome in clinical practice. Here we highlight the recent progression in PSC technologies for the regeneration of injured heart. We review novel strategies that might overcome current obstacles in heart regenerative medicine, aiming at improving cell survival and functional integration after cell transplantation.

  12. Stem cell signaling. An integral program for tissue renewal and regeneration : Wnt signaling and stem cell control

    Clevers, Hans; Loh, Kyle M; Nusse, Roel

    2014-01-01

    Stem cells fuel tissue development, renewal, and regeneration, and these activities are controlled by the local stem cell microenvironment, the "niche." Wnt signals emanating from the niche can act as self-renewal factors for stem cells in multiple mammalian tissues. Wnt proteins are lipid-modified,

  13. Neuromast hair cells retain the capacity of regeneration during heavy metal exposure.

    Montalbano, G; Capillo, G; Laurà, R; Abbate, F; Levanti, M; Guerrera, M C; Ciriaco, E; Germanà, A

    2018-07-01

    The neuromast is the morphological unit of the lateral line of fishes and is composed of a cluster of central sensory cells (hair cells) surrounded by support and mantle cells. Heavy metals exposure leads to disruption of hair cells within the neuromast. It is well known that the zebrafish has the ability to regenerate the hair cells after damage caused by toxicants. The process of regeneration depends on proliferation, differentiation and cellular migration of sensory and non-sensory progenitor cells. Therefore, our study was made in order to identify which cellular types are involved in the complex process of regeneration during heavy metals exposure. For this purpose, adult zebrafish were exposed to various heavy metals (Arsenic, cadmium and zinc) for 72h. After acute (24h) exposure, immunohistochemical localization of S100 (a specific marker for hair cells) in the neuromasts highlighted the hair cells loss. The immunoreaction for Sox2 (a specific marker for stem cells), at the same time, was observed in the support and mantle cells, after exposure to arsenic and cadmium, while only in the support cells after exposure to zinc. After chronic (72h) exposure the hair cells were regenerated, showing an immunoreaction for S100 protein. At the same exposure time to the three metals, a Sox2 immunoreaction was expressed in support and mantle cells. Our results showed for the first time the regenerative capacity of hair cells, not only after, but also during exposure to heavy metals, demonstrated by the presence of different stem cells that can diversify in hair cells. Copyright © 2018 Elsevier GmbH. All rights reserved.

  14. A living thick nanofibrous implant bifunctionalized with active growth factor and stem cells for bone regeneration

    Eap S

    2015-02-01

    Full Text Available Sandy Eap,1,2,* Laetitia Keller,1–3,* Jessica Schiavi,1,2 Olivier Huck,1,2 Leandro Jacomine,4 Florence Fioretti,1,2 Christian Gauthier,4 Victor Sebastian,1,3,5 Pascale Schwinté,1,2 Nadia Benkirane-Jessel1,21INSERM, UMR 1109, Osteoarticular and Dental Regenerative Nanomedicine Laboratory, FMTS, Faculté de Médecine, Strasbourg, France; 2Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, France; 3Department of Chemical Engineering, Aragon Nanoscience Institute, University of Zaragoza, Zaragoza, Spain; 4CNRS (National Center for Scientific Research, ICS (Charles Sadron Institute, Strasbourg, France; 5Networking Research Center of Bioengineering, Biomaterials and Nanomedicine, Zaragoza, Spain*These authors contributed equally to this workAbstract: New-generation implants focus on robust, durable, and rapid tissue regeneration to shorten recovery times and decrease risks of postoperative complications for patients. Herein, we describe a new-generation thick nanofibrous implant functionalized with active containers of growth factors and stem cells for regenerative nanomedicine. A thick electrospun poly(ε-caprolactone nanofibrous implant (from 700 µm to 1 cm thick was functionalized with chitosan and bone morphogenetic protein BMP-7 as growth factor using layer-by-layer technology, producing fish scale-like chitosan/BMP-7 nanoreservoirs. This extracellular matrix-mimicking scaffold enabled in vitro colonization and bone regeneration by human primary osteoblasts, as shown by expression of osteocalcin, osteopontin, and bone sialoprotein (BSPII, 21 days after seeding. In vivo implantation in mouse calvaria defects showed significantly more newly mineralized extracellular matrix in the functionalized implant compared to a bare scaffold after 30 days’ implantation, as shown by histological scanning electron microscopy/energy dispersive X-ray microscopy study and calcein injection. We have as well bifunctionalized our BMP-7

  15. Akirin1 (Mighty), a novel promyogenic factor regulates muscle regeneration and cell chemotaxis

    Salerno, Monica Senna; Dyer, Kelly; Bracegirdle, Jeremy; Platt, Leanne; Thomas, Mark; Siriett, Victoria [Functional Muscle Genomics, AgResearch, Hamilton (New Zealand); Kambadur, Ravi [Functional Muscle Genomics, AgResearch, Hamilton (New Zealand); School of Biological Sciences, Nanyang Technological University, Singapore (Singapore); Sharma, Mridula, E-mail: bchmridu@nus.edu.sg [Functional Muscle Genomics, AgResearch, Hamilton (New Zealand)

    2009-07-15

    Akirin1 (Mighty) is a downstream target gene of myostatin and has been shown to be a promyogenic factor. Although expressed in many tissues, akirin1 is negatively regulated by myostatin specifically in skeletal muscle tissue. In this manuscript we have characterized the possible function of akirin1 in postnatal muscle growth. Molecular and immunohistological analyses indicated that while low levels of akirin1 are associated with quiescent satellite cells (SC), higher levels of akirin1 are detected in activated proliferating SC indicating that akirin1 could be associated with satellite cell activation. In addition to SC, macrophages also express akirin1, and increased expression of akirin1 resulted in more efficient chemotaxis of both macrophages and myoblasts. Akirin1 appears to regulate chemotaxis of both macrophages and myoblasts by reorganising actin cytoskeleton, leading to more efficient lamellipodia formation via a PI3 kinase dependent pathway. Expression analysis during muscle regeneration also indicated that akirin1 expression is detected very early (day 2) in regenerating muscle, and expression gradually peaks to coincide the nascent myotube formation stage of muscle regeneration. Based on these results we propose that akirin1 could be acting as a transducer of early signals of muscle regeneration. Thus, we speculate that myostatin regulates key steps of muscle regeneration including chemotaxis of inflammatory cells, SC activation and migration through akirin1.

  16. Akirin1 (Mighty), a novel promyogenic factor regulates muscle regeneration and cell chemotaxis

    Salerno, Monica Senna; Dyer, Kelly; Bracegirdle, Jeremy; Platt, Leanne; Thomas, Mark; Siriett, Victoria; Kambadur, Ravi; Sharma, Mridula

    2009-01-01

    Akirin1 (Mighty) is a downstream target gene of myostatin and has been shown to be a promyogenic factor. Although expressed in many tissues, akirin1 is negatively regulated by myostatin specifically in skeletal muscle tissue. In this manuscript we have characterized the possible function of akirin1 in postnatal muscle growth. Molecular and immunohistological analyses indicated that while low levels of akirin1 are associated with quiescent satellite cells (SC), higher levels of akirin1 are detected in activated proliferating SC indicating that akirin1 could be associated with satellite cell activation. In addition to SC, macrophages also express akirin1, and increased expression of akirin1 resulted in more efficient chemotaxis of both macrophages and myoblasts. Akirin1 appears to regulate chemotaxis of both macrophages and myoblasts by reorganising actin cytoskeleton, leading to more efficient lamellipodia formation via a PI3 kinase dependent pathway. Expression analysis during muscle regeneration also indicated that akirin1 expression is detected very early (day 2) in regenerating muscle, and expression gradually peaks to coincide the nascent myotube formation stage of muscle regeneration. Based on these results we propose that akirin1 could be acting as a transducer of early signals of muscle regeneration. Thus, we speculate that myostatin regulates key steps of muscle regeneration including chemotaxis of inflammatory cells, SC activation and migration through akirin1.

  17. Deletion of the Imprinted Gene Grb10 Promotes Hematopoietic Stem Cell Self-Renewal and Regeneration.

    Yan, Xiao; Himburg, Heather A; Pohl, Katherine; Quarmyne, Mamle; Tran, Evelyn; Zhang, Yurun; Fang, Tiancheng; Kan, Jenny; Chao, Nelson J; Zhao, Liman; Doan, Phuong L; Chute, John P

    2016-11-01

    Imprinted genes are differentially expressed by adult stem cells, but their functions in regulating adult stem cell fate are incompletely understood. Here we show that growth factor receptor-bound protein 10 (Grb10), an imprinted gene, regulates hematopoietic stem cell (HSC) self-renewal and regeneration. Deletion of the maternal allele of Grb10 in mice (Grb10 m/+ mice) substantially increased HSC long-term repopulating capacity, as compared to that of Grb10 +/+ mice. After total body irradiation (TBI), Grb10 m/+ mice demonstrated accelerated HSC regeneration and hematopoietic reconstitution, as compared to Grb10 +/+ mice. Grb10-deficient HSCs displayed increased proliferation after competitive transplantation or TBI, commensurate with upregulation of CDK4 and Cyclin E. Furthermore, the enhanced HSC regeneration observed in Grb10-deficient mice was dependent on activation of the Akt/mTORC1 pathway. This study reveals a function for the imprinted gene Grb10 in regulating HSC self-renewal and regeneration and suggests that the inhibition of Grb10 can promote hematopoietic regeneration in vivo. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  18. mTOR is necessary for proper satellite cell activity and skeletal muscle regeneration

    Zhang, Pengpeng [Key Laboratory of Swine Genetics and Breeding of Agricultural Ministry & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); Liang, Xinrong; Shan, Tizhong [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); Jiang, Qinyang [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States); College of Animal Science and Technology, Guangxi University, Nanning 530004 (China); Deng, Changyan [Key Laboratory of Swine Genetics and Breeding of Agricultural Ministry & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Zheng, Rong, E-mail: zhengrong@mail.hzau.edu.cn [Key Laboratory of Swine Genetics and Breeding of Agricultural Ministry & Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan 430070 (China); Kuang, Shihuan, E-mail: skuang@purdue.edu [Department of Animal Sciences, Purdue University, West Lafayette, IN 47907 (United States)

    2015-07-17

    The serine/threonine kinase mammalian target of rapamycin (mTOR) is a key regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive deletion of Mtor gene results in embryonic lethality, the function of mTOR in muscle stem cells (satellite cells) and skeletal muscle regeneration remains to be determined. In this study, we established a satellite cell specific Mtor conditional knockout (cKO) mouse model by crossing Pax7{sup CreER} and Mtor{sup flox/flox} mice. Skeletal muscle regeneration after injury was severely compromised in the absence of Mtor, indicated by increased number of necrotic myofibers infiltrated by Evans blue dye, and reduced number and size of regenerated myofibers in the Mtor cKO mice compared to wild type (WT) littermates. To dissect the cellular mechanism, we analyzed satellite cell-derived primary myoblasts grown on single myofibers or adhered to culture plates. The Mtor cKO myoblasts exhibited defective proliferation and differentiation kinetics when compared to myoblasts derived from WT littermates. At the mRNA and protein levels, the Mtor cKO myoblasts expressed lower levels of key myogenic determinant genes Pax7, Myf5, Myod, Myog than did the WT myoblasts. These results suggest that mTOR is essential for satellite cell function and skeletal muscle regeneration through controlling the expression of myogenic genes. - Highlights: • Pax7{sup CreER} was used to delete Mtor gene in satellite cells. • Satellite cell specific deletion of Mtor impairs muscle regeneration. • mTOR is necessary for satellite cell proliferation and differentiation. • Deletion of Mtor leads to reduced expression of key myogenic genes.

  19. mTOR is necessary for proper satellite cell activity and skeletal muscle regeneration

    Zhang, Pengpeng; Liang, Xinrong; Shan, Tizhong; Jiang, Qinyang; Deng, Changyan; Zheng, Rong; Kuang, Shihuan

    2015-01-01

    The serine/threonine kinase mammalian target of rapamycin (mTOR) is a key regulator of protein synthesis, cell proliferation and energy metabolism. As constitutive deletion of Mtor gene results in embryonic lethality, the function of mTOR in muscle stem cells (satellite cells) and skeletal muscle regeneration remains to be determined. In this study, we established a satellite cell specific Mtor conditional knockout (cKO) mouse model by crossing Pax7 CreER and Mtor flox/flox mice. Skeletal muscle regeneration after injury was severely compromised in the absence of Mtor, indicated by increased number of necrotic myofibers infiltrated by Evans blue dye, and reduced number and size of regenerated myofibers in the Mtor cKO mice compared to wild type (WT) littermates. To dissect the cellular mechanism, we analyzed satellite cell-derived primary myoblasts grown on single myofibers or adhered to culture plates. The Mtor cKO myoblasts exhibited defective proliferation and differentiation kinetics when compared to myoblasts derived from WT littermates. At the mRNA and protein levels, the Mtor cKO myoblasts expressed lower levels of key myogenic determinant genes Pax7, Myf5, Myod, Myog than did the WT myoblasts. These results suggest that mTOR is essential for satellite cell function and skeletal muscle regeneration through controlling the expression of myogenic genes. - Highlights: • Pax7 CreER was used to delete Mtor gene in satellite cells. • Satellite cell specific deletion of Mtor impairs muscle regeneration. • mTOR is necessary for satellite cell proliferation and differentiation. • Deletion of Mtor leads to reduced expression of key myogenic genes

  20. Visual selection and maintenance of the cell lines with high plant regeneration ability and low ploidy level in Dianthus acicularis by monitoring with flow cytometry analysis.

    Shiba, Tomonori; Mii, Masahiro

    2005-12-01

    Efficient plant regeneration system from cell suspension cultures was established in D. acicularis (2n=90) by monitoring ploidy level and visual selection of the cultures. The ploidy level of the cell cultures closely related to the shoot regeneration ability. The cell lines comprising original ploidy levels (2C+4C cells corresponding to DNA contents of G1 and G2 cells of diploid plant, respectively) showed high regeneration ability, whereas those containing the cells with 8C or higher DNA C-values showed low or no regeneration ability. The highly regenerable cell lines thus selected consisted of compact cell clumps with yellowish color and relatively moderate growth, suggesting that it is possible to select visually the highly regenerable cell lines with the original ploidy level. All the regenerated plantlets from the highly regenerable cell cultures exhibited normal phenotypes and no variations in ploidy level were observed by flow cytometry (FCM) analysis.

  1. Potential Roles of Dental Pulp Stem Cells in Neural Regeneration and Repair

    Luo, Lihua; Wang, Xiaoyan; Key, Brian; Lee, Bae Hoon

    2018-01-01

    This review summarizes current advances in dental pulp stem cells (DPSCs) and their potential applications in the nervous diseases. Injured adult mammalian nervous system has a limited regenerative capacity due to an insufficient pool of precursor cells in both central and peripheral nervous systems. Nerve growth is also constrained by inhibitory factors (associated with central myelin) and barrier tissues (glial scarring). Stem cells, possessing the capacity of self-renewal and multicellular differentiation, promise new therapeutic strategies for overcoming these impediments to neural regeneration. Dental pulp stem cells (DPSCs) derive from a cranial neural crest lineage, retain a remarkable potential for neuronal differentiation, and additionally express multiple factors that are suitable for neuronal and axonal regeneration. DPSCs can also express immunomodulatory factors that stimulate formation of blood vessels and enhance regeneration and repair of injured nerve. These unique properties together with their ready accessibility make DPSCs an attractive cell source for tissue engineering in injured and diseased nervous systems. In this review, we interrogate the neuronal differentiation potential as well as the neuroprotective, neurotrophic, angiogenic, and immunomodulatory properties of DPSCs and its application in the injured nervous system. Taken together, DPSCs are an ideal stem cell resource for therapeutic approaches to neural repair and regeneration in nerve diseases. PMID:29853908

  2. Adenosine signaling promotes regeneration of pancreatic β-cells in vivo

    Andersson, Olov; Adams, Bruce A.; Yoo, Daniel; Ellis, Gregory C.; Gut, Philipp; Anderson, Ryan M.; German, Michael S.; Stainier, Didier Y. R.

    2012-01-01

    Diabetes can be controlled with insulin injections, but a curative approach that restores the number of insulin-producing β-cells is still needed. Using a zebrafish model of diabetes, we screened ~7000 small molecules to identify enhancers of β-cell regeneration. The compounds we identified converge on the adenosine signaling pathway and include exogenous agonists and compounds that inhibit degradation of endogenously produced adenosine. The most potent enhancer of β-cell regeneration was the adenosine agonist 5′-N-Ethylcarboxamidoadenosine (NECA), which acting through the adenosine receptor A2aa increased β-cell proliferation and accelerated restoration of normoglycemia in zebrafish. Despite markedly stimulating β-cell proliferation during regeneration, NECA had only a modest effect during development. The proliferative and glucose-lowering effect of NECA was confirmed in diabetic mice, suggesting an evolutionarily conserved role for adenosine in β-cell regeneration. With this whole-organism screen, we identified components of the adenosine pathway that could be therapeutically targeted for the treatment of diabetes. PMID:22608007

  3. Distribution and time course of hair cell regeneration in the pigeon utricle

    Dye, B. J.; Frank, T. C.; Newlands, S. D.; Dickman, J. D.

    1999-01-01

    Vestibular and cochlear regeneration following ototoxic insult from aminoglycoside antibiotics has been well documented, particularly in birds. In the present study, intraotic application of a 2 mg streptomycin paste was used to achieve complete vestibular hair cell destruction in pigeons (Columba livia) while preserving regenerative ability. Scanning electron microscopy was used to quantify hair cell density longitudinally during regeneration in three different utricular macula locations, including the striola, central and peripheral regions. The utricular epithelium was void of stereocilia (indicating hair cell loss) at 4 days after intraotic treatment with streptomycin. At 2 weeks the stereocilia began to appear randomly and mostly in an immature form. However, when present most kinocilia were polarized toward the developing striola. Initially, regeneration occurred more rapidly in the central and peripheral regions of the utricle as compared to the striola. As regeneration proceeded from 2 to 12 weeks, hair cell density in the striola region equaled the density noted in the central and peripheral regions. At 24 weeks, hair cell density of the central and peripheral regions was equal to normal values, however the striola region had a slightly greater hair cell density than that observed for normal animals.

  4. Peripheral Nerve Regeneration by Secretomes of Stem Cells from Human Exfoliated Deciduous Teeth.

    Sugimura-Wakayama, Yukiko; Katagiri, Wataru; Osugi, Masashi; Kawai, Takamasa; Ogata, Kenichi; Sakaguchi, Kohei; Hibi, Hideharu

    2015-11-15

    Peripheral nerve regeneration across nerve gaps is often suboptimal, with poor functional recovery. Stem cell transplantation-based regenerative therapy is a promising approach for axon regeneration and functional recovery of peripheral nerve injury; however, the mechanisms remain controversial and unclear. Recent studies suggest that transplanted stem cells promote tissue regeneration through a paracrine mechanism. We investigated the effects of conditioned media derived from stem cells from human exfoliated deciduous teeth (SHED-CM) on peripheral nerve regeneration. In vitro, SHED-CM-treated Schwann cells exhibited significantly increased proliferation, migration, and the expression of neuron-, extracellular matrix (ECM)-, and angiogenesis-related genes. SHED-CM stimulated neuritogenesis of dorsal root ganglia and increased cell viability. Similarly, SHED-CM enhanced tube formation in an angiogenesis assay. In vivo, a 10-mm rat sciatic nerve gap model was bridged by silicon conduits containing SHED-CM or serum-free Dulbecco's modified Eagle's medium. Light and electron microscopy confirmed that the number of myelinated axons and axon-to-fiber ratio (G-ratio) were significantly higher in the SHED-CM group at 12 weeks after nerve transection surgery. The sciatic functional index (SFI) and gastrocnemius (target muscle) wet weight ratio demonstrated functional recovery. Increased compound muscle action potentials and increased SFI in the SHED-CM group suggested sciatic nerve reinnervation of the target muscle and improved functional recovery. We also observed reduced muscle atrophy in the SHED-CM group. Thus, SHEDs may secrete various trophic factors that enhance peripheral nerve regeneration through multiple mechanisms. SHED-CM may therefore provide a novel therapy that creates a more desirable extracellular microenvironment for peripheral nerve regeneration.

  5. Maintained expression of the planar cell polarity molecule Vangl2 and reformation of hair cell orientation in the regenerating inner ear.

    Warchol, Mark E; Montcouquiol, Mireille

    2010-09-01

    The avian inner ear possesses a remarkable ability to regenerate sensory hair cells after ototoxic injury. Regenerated hair cells possess phenotypes and innervation that are similar to those found in the undamaged ear, but little is known about the signaling pathways that guide hair cell differentiation during the regenerative process. The aim of the present study was to examine the factors that specify the orientation of hair cell stereocilia bundles during regeneration. Using organ cultures of the chick utricle, we show that hair cells are properly oriented after having regenerated entirely in vitro and that orientation is not affected by surgical removal of the striolar reversal zone. These results suggest that the orientation of regenerating stereocilia is not guided by the release of a diffusible morphogen from the striolar reversal zone but is specified locally within the regenerating sensory organ. In order to determine the nature of the reorientation cues, we examined the expression patterns of the core planar cell polarity molecule Vangl2 in the normal and regenerating utricle. We found that Vangl2 is asymmetrically expressed on cells within the sensory epithelium and that this expression pattern is maintained after ototoxic injury and throughout regeneration. Notably, treatment with a small molecule inhibitor of c-Jun-N-terminal kinase disrupted the orientation of regenerated hair cells. Both of these results are consistent with the hypothesis that noncanonical Wnt signaling guides hair cell orientation during regeneration.

  6. Cell and biomolecule delivery for tissue repair and regeneration in the central nervous system.

    Elliott Donaghue, Irja; Tam, Roger; Sefton, Michael V; Shoichet, Molly S

    2014-09-28

    Tissue engineering frequently involves cells and scaffolds to replace damaged or diseased tissue. It originated, in part, as a means of effecting the delivery of biomolecules such as insulin or neurotrophic factors, given that cells are constitutive producers of such therapeutic agents. Thus cell delivery is intrinsic to tissue engineering. Controlled release of biomolecules is also an important tool for enabling cell delivery since the biomolecules can enable cell engraftment, modulate inflammatory response or otherwise benefit the behavior of the delivered cells. We describe advances in cell and biomolecule delivery for tissue regeneration, with emphasis on the central nervous system (CNS). In the first section, the focus is on encapsulated cell therapy. In the second section, the focus is on biomolecule delivery in polymeric nano/microspheres and hydrogels for the nerve regeneration and endogenous cell stimulation. In the third section, the focus is on combination strategies of neural stem/progenitor cell or mesenchymal stem cell and biomolecule delivery for tissue regeneration and repair. In each section, the challenges and potential solutions associated with delivery to the CNS are highlighted. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. Regeneration of Tissues and Organs Using Autologous Cells

    Anthony Atala

    2010-04-28

    native tissue environment to ensure tissue integration, maturation, and survival. Other long-term benefits of this research are likely to be cell-based drug delivery mechanisms, intelligent biomaterials, bio-nano technologies, as well as controlled delivery using advances in materials science. The major challenges to the goal of producing tissues and organs for transplantation and reconstruction are three-fold and will form the basis for the goals of this research. These include (1) Identifying sources of autologous cells and developing methods to expand them in large number in vitro, (2) Providing vascular support for growing constructs, and (3) Developing biomaterials and bioreactor systems that mimic the native tissue environment.

  8. Slow-cycling stem cells in hydra contribute to head regeneration

    Niraimathi Govindasamy

    2014-11-01

    Full Text Available Adult stem cells face the challenge of maintaining tissue homeostasis by self-renewal while maintaining their proliferation potential over the lifetime of an organism. Continuous proliferation can cause genotoxic/metabolic stress that can compromise the genomic integrity of stem cells. To prevent stem cell exhaustion, highly proliferative adult tissues maintain a pool of quiescent stem cells that divide only in response to injury and thus remain protected from genotoxic stress. Hydra is a remarkable organism with highly proliferative stem cells and ability to regenerate at whole animal level. Intriguingly, hydra does not display consequences of high proliferation, such as senescence or tumour formation. In this study, we investigate if hydra harbours a pool of slow-cycling stem cells that could help prevent undesirable consequences of continuous proliferation. Hydra were pulsed with the thymidine analogue 5-ethynyl-2′-deoxyuridine (EdU and then chased in the absence of EdU to monitor the presence of EdU-retaining cells. A significant number of undifferentiated cells of all three lineages in hydra retained EdU for about 8–10 cell cycles, indicating that these cells did not enter cell cycle. These label-retaining cells were resistant to hydroxyurea treatment and were predominantly in the G2 phase of cell cycle. Most significantly, similar to mammalian quiescent stem cells, these cells rapidly entered cell division during head regeneration. This study shows for the first time that, contrary to current beliefs, cells in hydra display heterogeneity in their cell cycle potential and the slow-cycling cells in this population enter cell cycle during head regeneration. These results suggest an early evolution of slow-cycling stem cells in multicellular animals.

  9. Cell-derived micro-environment helps dental pulp stem cells promote dental pulp regeneration.

    Zhang, Xuexin; Li, Hui; Sun, Jingjing; Luo, Xiangyou; Yang, Hefeng; Xie, Li; Yang, Bo; Guo, Weihua; Tian, Weidong

    2017-10-01

    The function of the dental pulp is closely connected to the extracellular matrix (ECM) structure, and ECM has received significant attention due to its biological functions for regulating cells. As such, the interaction between the ECM niche and cells is worth exploring for potential clinical uses. In this study, dental pulp stem cell (DPSC)-derived ECM (DPM) was prepared through cell culture and decellularization to function as the cell niche, and changes in DPSC behaviour and histological analysis of dental pulp tissue regeneration were evaluated following the DPM culture. DPM promoted the replication of DPSCs and exhibited retention of their mineralization. Then, the DPM-based culture strategy under odontogenic culture medium was further investigated, and the mineralization-related markers showed that DPSCs were regulated towards odontogenic differentiation. Dental pulp-like tissue with well-arranged ECM was harvested after a 2-month subcutaneous implantation in nude mice with DPM application. Additionally, DPSCs cultured on the plastic culture surface showed the up-regulation of mineralization makers in vitro, but there was a disorder in matrix formation and mineralization when the cells were cultured in vivo. DPM-based cultivation could serve as a cell niche and modulate DPSC behaviour, and this method also provided an alternative to harvest tissue-specific ECM and provided a strategy for ECM-cell interaction. © 2017 John Wiley & Sons Ltd.

  10. Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts

    He, Yingzi; Cai, Chengfu; Tang, Dongmei; Sun, Shan; Li, Huawei

    2014-01-01

    In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, non-mammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well-suited for studying hair cell development and regeneration. Histone deacetylase (HDAC) activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU) incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA) or valproic acid (VPA) increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21Cip1 and p27Kip1 expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line. PMID:25431550

  11. Effect of histone deacetylase inhibitors trichostatin A and valproic acid on hair cell regeneration in zebrafish lateral line neuromasts

    Yingzi eHe

    2014-11-01

    Full Text Available In humans, auditory hair cells are not replaced when injured. Thus, cochlear hair cell loss causes progressive and permanent hearing loss. Conversely, nonmammalian vertebrates are capable of regenerating lost sensory hair cells. The zebrafish lateral line has numerous qualities that make it well suited for studying hair cell development and regeneration. Histone deacetylase (HDAC activity has been shown to have an important role in regenerative processes in vertebrates, but its function in hair cell regeneration in vivo is not fully understood. Here, we have examined the role of HDAC activity in hair cell regeneration in the zebrafish lateral line. We eliminated lateral line hair cells of 5-day post-fertilization larvae using neomycin and then treated the larvae with HDAC inhibitors. To assess hair cell regeneration, we used 5-bromo-2-deoxyuridine (BrdU incorporation in zebrafish larvae to label mitotic cells after hair cell loss. We found that pharmacological inhibition of HDACs using trichostatin A (TSA or valproic acid (VPA increased histone acetylation in the regenerated neuromasts following neomycin-induced damage. We also showed that treatment with TSA or VPA decreased the number of supporting cells and regenerated hair cells in response to hair cell damage. Additionally, BrdU immunostaining and western blot analysis showed that TSA or VPA treatment caused a significant decrease in the percentage of S-phase cells and induced p21Cip1 and p27Kip1 expression, both of which are likely to explain the decrease in the amount of newly regenerated hair cells in treated embryos. Finally, we showed that HDAC inhibitors induced no observable cell death in neuromasts as measured by cleaved caspase-3 immunohistochemistry and western blot analysis. Taken together, our results demonstrate that HDAC activity has an important role in the regeneration of hair cells in the lateral line.

  12. Human Umbilical Cord MSCs as New Cell Sources for Promoting Periodontal Regeneration in Inflammatory Periodontal Defect.

    Shang, Fengqing; Liu, Shiyu; Ming, Leiguo; Tian, Rong; Jin, Fang; Ding, Yin; Zhang, Yongjie; Zhang, Hongmei; Deng, Zhihong; Jin, Yan

    2017-01-01

    Human periodontal ligament stem cells (hPDLSCs) transplantation represents a promising approach for periodontal regeneration; however, the cell source is limited due to the invasive procedure required for cell isolation. As human umbilical cord mesenchymal stem cells (hUCMSCs) can be harvested inexpensively and inexhaustibly, here we evaluated the regenerative potentials of hUCMSCs as compared with hPDLSCs to determine whether hUCMSCs could be used as new cell sources for periodontal regeneration. Methods The characteristics of hUCMSCs, including multi-differentiation ability and anti-inflammatory capability, were determined by comparison with hPDLSCs. We constructed cell aggregates (CA) using hUCMSCs and hPDLSCs respectively. Then hPDLSCs-CA and hUCMSCs-CA were combined with β-tricalcium phosphate bioceramic (β-TCP) respectively and their regenerative potentials were determined in a rat inflammatory periodontal defect model. Results hPDLSCs showed higher osteogenic differentiation potentials than hUCMSCs. Meanwhile, hUCMSCs showed higher extracellular matrix secretion and anti-inflammatory abilities than hPDLSCs. Similar to hPDLSCs, hUCMSCs were able to contribute to regeneration of both soft and hard periodontal tissues under inflammatory periodontitis condition. There were more newly formed bone and periodontal ligaments in hPDLSCs and hUCMSCs groups than in non-cell treated group. Moreover, no significant differences of regenerative promoting effects between hPDLSCs and hUCMSCs were found. Conclusion : hUCMSCs generated similar promoting effects on periodontal regeneration compared with hPDLSCs, and can be used as new cell sources for periodontal regeneration.

  13. JNK Controls the Onset of Mitosis in Planarian Stem Cells and Triggers Apoptotic Cell Death Required for Regeneration and Remodeling

    Almuedo-Castillo, María; Crespo, Xenia; Seebeck, Florian; Bartscherer, Kerstin; Salò, Emili; Adell, Teresa

    2014-01-01

    Regeneration of lost tissues depends on the precise interpretation of molecular signals that control and coordinate the onset of proliferation, cellular differentiation and cell death. However, the nature of those molecular signals and the mechanisms that integrate the cellular responses remain largely unknown. The planarian flatworm is a unique model in which regeneration and tissue renewal can be comprehensively studied in vivo. The presence of a population of adult pluripotent stem cells combined with the ability to decode signaling after wounding enable planarians to regenerate a complete, correctly proportioned animal within a few days after any kind of amputation, and to adapt their size to nutritional changes without compromising functionality. Here, we demonstrate that the stress-activated c-jun–NH2–kinase (JNK) links wound-induced apoptosis to the stem cell response during planarian regeneration. We show that JNK modulates the expression of wound-related genes, triggers apoptosis and attenuates the onset of mitosis in stem cells specifically after tissue loss. Furthermore, in pre-existing body regions, JNK activity is required to establish a positive balance between cell death and stem cell proliferation to enable tissue renewal, remodeling and the maintenance of proportionality. During homeostatic degrowth, JNK RNAi blocks apoptosis, resulting in impaired organ remodeling and rescaling. Our findings indicate that JNK-dependent apoptotic cell death is crucial to coordinate tissue renewal and remodeling required to regenerate and to maintain a correctly proportioned animal. Hence, JNK might act as a hub, translating wound signals into apoptotic cell death, controlled stem cell proliferation and differentiation, all of which are required to coordinate regeneration and tissue renewal. PMID:24922054

  14. Mesenchymal stem cell-laden hybrid scaffold for regenerating subacute tympanic membrane perforation

    Jang, Chul Ho, E-mail: chulsavio@hanmail.net [Department of Otolaryngology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Ahn, SeungHyun [Department of Biomechatronic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon (Korea, Republic of); Lee, Jae Whi; Lee, Byeong Ha [School of Information and Communications, Gwangju Institute of Science and Technology, Gwangju (Korea, Republic of); Lee, Hyeongjin [Department of Biomechatronic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon (Korea, Republic of); Kim, GeunHyung, E-mail: gkimbme@skku.edu [Department of Biomechatronic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon (Korea, Republic of)

    2017-03-01

    Tympanic membrane (TM) perforation is one of the most common otology complications. To date, there has not been reported TM regeneration using bioprinted scaffold. The purpose of this study was to evaluate the efficacy and feasibility of bioprinted polycaprolactone/collagen/alginate-mesenchymal stem cell (PCAMSC) scaffolds for the regeneration of subacute TM perforation. Sprague-Dawley rats were used in an animal model of subacute TM perforation. In the experimental group (n = 7), bioprinted 3D PCAMSC scaffold was placed on the perforation. The control group (n = 7) were treated with polycaprolactone/collagen/alginate (PCA) scaffold. Healing time, acoustic-mechanical properties, and morphological analysis were performed by otoendoscopy, auditory brainstem response (ABR), single-point laser doppler vibrometer (LDV), optical coherence tomography (OCT), and light microscopic evaluation. The closure of the TM perforation was achieved in 100% of the experimental group vs. 72% of the control group, and this difference was statistically significant (p < 0.05). The ABR threshold at all frequencies of the experimental group was recovered to the normal level compared to the control group. TM vibration velocity in the experimental group recovered similar to the normal control level. The difference are very small and they are not statistically significant below 1 kHz (p = 0.074). By OCT and light microscopic examination, regenerated TM of the experimental group showed thickened fibrous and mucosal layer. In contrast, the control group showed well regenerated but less thickened than experimental group. From these results, the cell-laden PCAMSC scaffold offers a significant advantage in the TM regeneration in a rat subacute TM perforation model. It may offer attractive opportunities in the conservative clinical treatment. - Highlights: • MSCs-laden scaffold was fabricated using a centrifugal spinning and cell-printing process. • The cell-laden scaffold showed the outstanding

  15. Mesenchymal stem cell-laden hybrid scaffold for regenerating subacute tympanic membrane perforation

    Jang, Chul Ho; Ahn, SeungHyun; Lee, Jae Whi; Lee, Byeong Ha; Lee, Hyeongjin; Kim, GeunHyung

    2017-01-01

    Tympanic membrane (TM) perforation is one of the most common otology complications. To date, there has not been reported TM regeneration using bioprinted scaffold. The purpose of this study was to evaluate the efficacy and feasibility of bioprinted polycaprolactone/collagen/alginate-mesenchymal stem cell (PCAMSC) scaffolds for the regeneration of subacute TM perforation. Sprague-Dawley rats were used in an animal model of subacute TM perforation. In the experimental group (n = 7), bioprinted 3D PCAMSC scaffold was placed on the perforation. The control group (n = 7) were treated with polycaprolactone/collagen/alginate (PCA) scaffold. Healing time, acoustic-mechanical properties, and morphological analysis were performed by otoendoscopy, auditory brainstem response (ABR), single-point laser doppler vibrometer (LDV), optical coherence tomography (OCT), and light microscopic evaluation. The closure of the TM perforation was achieved in 100% of the experimental group vs. 72% of the control group, and this difference was statistically significant (p < 0.05). The ABR threshold at all frequencies of the experimental group was recovered to the normal level compared to the control group. TM vibration velocity in the experimental group recovered similar to the normal control level. The difference are very small and they are not statistically significant below 1 kHz (p = 0.074). By OCT and light microscopic examination, regenerated TM of the experimental group showed thickened fibrous and mucosal layer. In contrast, the control group showed well regenerated but less thickened than experimental group. From these results, the cell-laden PCAMSC scaffold offers a significant advantage in the TM regeneration in a rat subacute TM perforation model. It may offer attractive opportunities in the conservative clinical treatment. - Highlights: • MSCs-laden scaffold was fabricated using a centrifugal spinning and cell-printing process. • The cell-laden scaffold showed the outstanding

  16. Patient-specific cardiovascular progenitor cells derived from integration-free induced pluripotent stem cells for vascular tissue regeneration.

    Hu, Jiang; Wang, Yongyu; Jiao, Jiao; Liu, Zhongning; Zhao, Chao; Zhou, Zhou; Zhang, Zhanpeng; Forde, Kaitlynn; Wang, Lunchang; Wang, Jiangang; Baylink, David J; Zhang, Xiao-Bing; Gao, Shaorong; Yang, Bo; Chen, Y Eugene; Ma, Peter X

    2015-12-01

    Tissue-engineered blood vessels (TEBVs) are promising in regenerating a live vascular replacement. However, the vascular cell source is limited, and it is crucial to develop a scaffold that accommodates new type of vascular progenitor cells and facilitates in vivo lineage specification of the cells into functional vascular smooth muscle cells (VSMCs) to regenerate vascular tissue. In the present study, integration-free human induced pluripotent stem cells (hiPSCs) were established from patient peripheral blood mononuclear cells through episomal vector nucleofection of reprogramming factors. The established hiPSCs were then induced into mesoderm-originated cardiovascular progenitor cells (CVPCs) with a highly efficient directed lineage specification method. The derived CVPCs were demonstrated to be able to differentiate into functional VSMCs. Subcutaneous implantation of CVPCs seeded on macroporous nanofibrous poly(l-lactide) scaffolds led to in vivo VSMC lineage specification and matrix deposition inside the scaffolds. In summary, we established integration-free patient-specific hiPSCs from peripheral blood mononuclear cells, derived CVPCs through directed lineage specification, and developed an advanced scaffold for these progenitor cells to further differentiate in vivo into VSMCs and regenerate vascular tissue in a subcutaneous implantation model. This study has established an efficient patient-specific approach towards in vivo regeneration of vascular tissue. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Strategies to Optimize Adult Stem Cell Therapy for Tissue Regeneration

    Shan Liu

    2016-06-01

    Full Text Available Stem cell therapy aims to replace damaged or aged cells with healthy functioning cells in congenital defects, tissue injuries, autoimmune disorders, and neurogenic degenerative diseases. Among various types of stem cells, adult stem cells (i.e., tissue-specific stem cells commit to becoming the functional cells from their tissue of origin. These cells are the most commonly used in cell-based therapy since they do not confer risk of teratomas, do not require fetal stem cell maneuvers and thus are free of ethical concerns, and they confer low immunogenicity (even if allogenous. The goal of this review is to summarize the current state of the art and advances in using stem cell therapy for tissue repair in solid organs. Here we address key factors in cell preparation, such as the source of adult stem cells, optimal cell types for implantation (universal mesenchymal stem cells vs. tissue-specific stem cells, or induced vs. non-induced stem cells, early or late passages of stem cells, stem cells with endogenous or exogenous growth factors, preconditioning of stem cells (hypoxia, growth factors, or conditioned medium, using various controlled release systems to deliver growth factors with hydrogels or microspheres to provide apposite interactions of stem cells and their niche. We also review several approaches of cell delivery that affect the outcomes of cell therapy, including the appropriate routes of cell administration (systemic, intravenous, or intraperitoneal vs. local administration, timing for cell therapy (immediate vs. a few days after injury, single injection of a large number of cells vs. multiple smaller injections, a single site for injection vs. multiple sites and use of rodents vs. larger animal models. Future directions of stem cell-based therapies are also discussed to guide potential clinical applications.

  18. Regeneration of pancreatic non-β endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin.

    Yanqing Zhang

    Full Text Available The non-β endocrine cells in pancreatic islets play an essential counterpart and regulatory role to the insulin-producing β-cells in the regulation of blood-glucose homeostasis. While significant progress has been made towards the understanding of β-cell regeneration in adults, very little is known about the regeneration of the non-β endocrine cells such as glucagon-producing α-cells and somatostatin producing δ-cells. Previous studies have noted the increase of α-cell composition in diabetes patients and in animal models. It is thus our hypothesis that non-β-cells such as α-cells and δ-cells in adults can regenerate, and that the regeneration accelerates in diabetic conditions. To test this hypothesis, we examined islet cell composition in a streptozotocin (STZ-induced diabetes mouse model in detail. Our data showed the number of α-cells in each islet increased following STZ-mediated β-cell destruction, peaked at Day 6, which was about 3 times that of normal islets. In addition, we found δ-cell numbers doubled by Day 6 following STZ treatment. These data suggest α- and δ-cell regeneration occurred rapidly following a single diabetes-inducing dose of STZ in mice. Using in vivo BrdU labeling techniques, we demonstrated α- and δ-cell regeneration involved cell proliferation. Co-staining of the islets with the proliferating cell marker Ki67 showed α- and δ-cells could replicate, suggesting self-duplication played a role in their regeneration. Furthermore, Pdx1(+/Insulin(- cells were detected following STZ treatment, indicating the involvement of endocrine progenitor cells in the regeneration of these non-β cells. This is further confirmed by the detection of Pdx1(+/glucagon(+ cells and Pdx1(+/somatostatin(+ cells following STZ treatment. Taken together, our study demonstrated adult α- and δ-cells could regenerate, and both self-duplication and regeneration from endocrine precursor cells were involved in their regeneration.

  19. Muscle Satellite Cell Protein Teneurin-4 Regulates Differentiation During Muscle Regeneration.

    Ishii, Kana; Suzuki, Nobuharu; Mabuchi, Yo; Ito, Naoki; Kikura, Naomi; Fukada, So-Ichiro; Okano, Hideyuki; Takeda, Shin'ichi; Akazawa, Chihiro

    2015-10-01

    Satellite cells are maintained in an undifferentiated quiescent state, but during muscle regeneration they acquire an activated stage, and initiate to proliferate and differentiate as myoblasts. The transmembrane protein teneurin-4 (Ten-4) is specifically expressed in the quiescent satellite cells; however, its cellular and molecular functions remain unknown. We therefore aimed to elucidate the function of Ten-4 in muscle satellite cells. In the tibialis anterior (TA) muscle of Ten-4-deficient mice, the number and the size of myofibers, as well as the population of satellite cells, were reduced with/without induction of muscle regeneration. Furthermore, we found an accelerated activation of satellite cells in the regenerated Ten-4-deficient TA muscle. The cell culture analysis using primary satellite cells showed that Ten-4 suppressed the progression of myogenic differentiation. Together, our findings revealed that Ten-4 functions as a crucial player in maintaining the quiescence of muscle satellite cells. © 2015 The Authors STEM CELLS published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  20. Muscle Satellite Cell Protein Teneurin‐4 Regulates Differentiation During Muscle Regeneration

    Ishii, Kana; Suzuki, Nobuharu; Mabuchi, Yo; Ito, Naoki; Kikura, Naomi; Fukada, So‐ichiro; Okano, Hideyuki; Takeda, Shin'ichi

    2015-01-01

    Abstract Satellite cells are maintained in an undifferentiated quiescent state, but during muscle regeneration they acquire an activated stage, and initiate to proliferate and differentiate as myoblasts. The transmembrane protein teneurin‐4 (Ten‐4) is specifically expressed in the quiescent satellite cells; however, its cellular and molecular functions remain unknown. We therefore aimed to elucidate the function of Ten‐4 in muscle satellite cells. In the tibialis anterior (TA) muscle of Ten‐4‐deficient mice, the number and the size of myofibers, as well as the population of satellite cells, were reduced with/without induction of muscle regeneration. Furthermore, we found an accelerated activation of satellite cells in the regenerated Ten‐4‐deficient TA muscle. The cell culture analysis using primary satellite cells showed that Ten‐4 suppressed the progression of myogenic differentiation. Together, our findings revealed that Ten‐4 functions as a crucial player in maintaining the quiescence of muscle satellite cells. Stem Cells 2015;33:3017–3027 PMID:26013034

  1. Serum Proteases Potentiate BMP-Induced Cell Cycle Re-entry of Dedifferentiating Muscle Cells during Newt Limb Regeneration

    Wagner, Ines; Wang, Heng; Weissert, Philipp M.; Straube, Werner L.; Shevchenko, Anna; Gentzel, Marc; Brito, Goncalo; Tazaki, Akira; Oliveira, Catarina; Sugiura, Takuji; Shevchenko, Andrej; Simon, Andras; Drechsel, David N.; Tanaka, Elly M.

    2017-01-01

    Limb amputation in the newt induces myofibers to dedifferentiate and re-enter the cell cycle to generate proliferative myogenic precursors in the regeneration blastema. Here we show that bone morphogenetic proteins (BMPs) and mature BMPs that have been further cleaved by serum proteases induce cell

  2. Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein

    Lu, Na [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Department of Otolaryngology and Program in Neuroscience, Harvard Medical School and Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114 (United States); Chen, Yan [Central Laboratory, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Wang, Zhengmin [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Institute of Biomedical Sciences, Fudan University, Shanghai 200032 (China); Chen, Guoling [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Lin, Qin [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Department of Otolaryngology, First Affiliated Hospital of Fujian Medical University, Otolaryngology Institute of Fujian Province, Fuzhou (China); Chen, Zheng-Yi, E-mail: Zheng-yi_chen@meei.harvard.edu [Department of Otolaryngology and Program in Neuroscience, Harvard Medical School and Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114 (United States); Li, Huawei, E-mail: hwli@shmu.edu.cn [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Institute of Biomedical Sciences, Fudan University, Shanghai 200032 (China)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer Shh activation in neonatal cochleae enhances sensory cell proliferation. Black-Right-Pointing-Pointer Proliferating supporting cells can transdifferentiate into hair cells. Black-Right-Pointing-Pointer Shh promotes proliferation by transiently modulating pRb activity. Black-Right-Pointing-Pointer Shh inhibits pRb by inhibiting transcription and increasing phosphorylation of pRb. -- Abstract: Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1. These results suggest that Shh signaling induces cell cycle re-entry in cochlear sensory epithelium and the production of new hair cells, in part by attenuating pRb function. This study provides an additional route to modulate pRb function with important implications in mammalian hair cell regeneration.

  3. Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein

    Lu, Na; Chen, Yan; Wang, Zhengmin; Chen, Guoling; Lin, Qin; Chen, Zheng-Yi; Li, Huawei

    2013-01-01

    Highlights: ► Shh activation in neonatal cochleae enhances sensory cell proliferation. ► Proliferating supporting cells can transdifferentiate into hair cells. ► Shh promotes proliferation by transiently modulating pRb activity. ► Shh inhibits pRb by inhibiting transcription and increasing phosphorylation of pRb. -- Abstract: Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1. These results suggest that Shh signaling induces cell cycle re-entry in cochlear sensory epithelium and the production of new hair cells, in part by attenuating pRb function. This study provides an additional route to modulate pRb function with important implications in mammalian hair cell regeneration.

  4. Meta-Analyses of Human Cell-Based Cardiac Regeneration Therapies

    Gyöngyösi, Mariann; Wojakowski, Wojciech; Navarese, Eliano P

    2016-01-01

    In contrast to multiple publication-based meta-analyses involving clinical cardiac regeneration therapy in patients with recent myocardial infarction, a recently published meta-analysis based on individual patient data reported no effect of cell therapy on left ventricular function or clinical...

  5. Hair follicle stem cell proliferation, Akt and Wnt signaling activation in TPA-induced hair regeneration.

    Qiu, Weiming; Lei, Mingxing; Zhou, Ling; Bai, Xiufeng; Lai, Xiangdong; Yu, Yu; Yang, Tian; Lian, Xiaohua

    2017-06-01

    Regeneration of hair follicles relies on activation of hair follicle stem cells during telogen to anagen transition process in hair cycle. This process is rigorously controlled by intrinsic and environmental factors. 12-o-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter, accelerates reentry of hair follicles into anagen phase. However, it is unclear that how TPA promotes the hair regeneration. In the present study, we topically applied TPA onto the dorsal skin of 2-month-old C57BL/6 female mice to examine the activity of hair follicle stem cells and alteration of signaling pathways during hair regeneration. We found that refractory telogen hair follicles entered anagen prematurely after TPA treatment, with the enhanced proliferation of CD34-positive hair follicle stem cells. Meanwhile, we observed Akt signaling was activated in epidermis, hair infundibulum, bulge and hair bulb, and Wnt signaling was also activated after hair follicle stem cells proliferation. Importantly, after overexpression of DKK1, a specific Wnt signaling inhibitor, the accelerated reentry of hair follicles into anagen induced by TPA was abolished. Our data indicated that TPA-induced hair follicle regeneration is associated with activation of Akt and Wnt/β-catenin signaling.

  6. Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration.

    Plikus, Maksim V; Mayer, Julie Ann; de la Cruz, Damon; Baker, Ruth E; Maini, Philip K; Maxson, Robert; Chuong, Cheng-Ming

    2008-01-17

    In the age of stem cell engineering it is critical to understand how stem cell activity is regulated during regeneration. Hairs are mini-organs that undergo cyclic regeneration throughout adult life, and are an important model for organ regeneration. Hair stem cells located in the follicle bulge are regulated by the surrounding microenvironment, or niche. The activation of such stem cells is cyclic, involving periodic beta-catenin activity. In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 in the dermis regulates this process. This BMP cycle is out of phase with the WNT/beta-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild-type host showed that follicles in donor and host can affect their cycling behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. These results show that BMPs may be the long-sought 'chalone' inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermo-regulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intra-cutaneous drug

  7. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration.

    Viswanathan, Preeti; Sharma, Yogeshwar; Gupta, Priya; Gupta, Sanjeev

    2018-03-05

    Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure. Cellular oxidative stress, DNA damage and cell proliferation events were investigated by mitochondrial membrane potential assays, flow cytometry, fluorescence staining, comet assays and spotted arrays for protein expression after acetaminophen exposures. In experimental groups with acetaminophen toxicity, impaired mitochondrial viability and substantial DNA damage were observed with rapid loss of cells in S and G2/M and cell cycle restrictions or even exit in the remainder. This resulted from altered expression of the DNA damage regulator, ATM and downstream transducers, which imposed G1/S checkpoint arrest, delayed entry into S and restricted G2 transit. Tissues from people with acute liver failure confirmed hepatic DNA damage and cell cycle-related lesions, including restrictions of hepatocytes in aneuploid states. Remarkably, treatment of cells with a cytoprotective cytokine reversed acetaminophen-induced restrictions to restore cycling. Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure. © 2018 John Wiley & Sons Ltd.

  8. Autologous dental pulp stem cells in periodontal regeneration: a case report.

    Aimetti, Mario; Ferrarotti, Francesco; Cricenti, Luca; Mariani, Giulia Maria; Romano, Federica

    2014-01-01

    Histologic findings in animal models suggest that the application of dental pulp stem cells (DPSCs) may promote periodontal regeneration in infrabony defects. This case report describes the clinical and radiographic regenerative potential of autologous DPSCs in the treatment of human noncontained intraosseous defects. A chronic periodontitis patient with one vital third molar requiring extraction was surgically treated. The third molar was extracted and used as an autologous DPSCs source to regenerate the infrabony defect on the mandibular right second premolar. At the 1-year examination, the defect was completely filled with bonelike tissue as confirmed through the reentry procedure.

  9. Study of inner ear and lateral line hair cell regeneration

    Piqué Borràs, Maria Riera

    2013-01-01

    Death of sensory hair cells in the inner ear results in two global health problems that millions of people around the world suffer: hearing loss and balance disorders. Hair cells convert sound vibrations and head movements into electrical signals that are conveyed to the brain, and as a result of aging, exposure to noise, modern drugs or genetic predisposition, hair cells die. In mammals, the great majority of hair cells are produced during embryogenesis, and hair cells that ar...

  10. Adipose stem cells for intervertebral disc regeneration: Current status and concepts for the future: Tissue Engineering Review Series

    Hoogendoorn, R.J.W.; Lu, Z.F.; Kroeze, R.J.; Bank, R.A.; Wuisman, P.I.; Helder, M.N.

    2008-01-01

    Introduction Degenerative disc disease and emerging biological treatment approaches Stem cell sources Integration of ASC-based regenerative medicine and surgery In vitro studies Animal models Cells in disc regeneration in vivo In vivo studies Perspective Conclusions Abstract New regenerative

  11. Brain and muscle Arnt-like 1 promotes skeletal muscle regeneration through satellite cell expansion

    Chatterjee, Somik [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yin, Hongshan [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Cardiovascular Medicine, Third Affiliated Hospital, Hebei Medical University, Shijiazhuang 050051, Hebei (China); Nam, Deokhwa [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Li, Yong [Department of Pediatric Surgery, Center for Stem Cell Research and Regenerative Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030 (United States); Ma, Ke, E-mail: kma@houstonmethodist.org [Center for Diabetes Research, Department of Medicine, Houston Methodist Research Institute, Houston, TX 77030 (United States)

    2015-02-01

    Circadian clock is an evolutionarily conserved timing mechanism governing diverse biological processes and the skeletal muscle possesses intrinsic functional clocks. Interestingly, although the essential clock transcription activator, Brain and muscle Arnt-like 1 (Bmal1), participates in maintenance of muscle mass, little is known regarding its role in muscle growth and repair. In this report, we investigate the in vivo function of Bmal1 in skeletal muscle regeneration using two muscle injury models. Bmal1 is highly up-regulated by cardiotoxin injury, and its genetic ablation significantly impairs regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction. A similarly defective regenerative response is observed in Bmal1-null mice as compared to wild-type controls upon freeze injury. Lack of satellite cell expansion accounts for the regeneration defect, as Bmal1{sup −/−} mice display significantly lower satellite cell number with nearly abolished induction of the satellite cell marker, Pax7. Furthermore, satellite cell-derived primary myoblasts devoid of Bmal1 display reduced growth and proliferation ex vivo. Collectively, our results demonstrate, for the first time, that Bmal1 is an integral component of the pro-myogenic response that is required for muscle repair. This mechanism may underlie its role in preserving adult muscle mass and could be targeted therapeutically to prevent muscle-wasting diseases. - Highlights: • Bmal1 is highly inducible by muscle injury and myogenic stimuli. • Genetic ablation of Bmal1 significantly impairs muscle regeneration. • Bmal1 promotes satellite cell expansion during muscle regeneration. • Bmal1-deficient primary myoblasts display attenuated growth and proliferation.

  12. Enhancement of organ regeneration in animal models by a stem cell-stimulating plant mixture.

    Kiss, István; Tibold, Antal; Halmosi, Róbert; Bartha, Eva; Koltai, Katalin; Orsós, Zsuzsanna; Bujdosó, László; Ember, István

    2010-06-01

    Adult stem cells play an important role in the regeneration of damaged organs. Attempts have already been made to enhance stem cell production by cytokines, in order to increase the improvement of cardiac functions after myocardial infarction. In our present study we investigated the possibility whether instead of cytokine injection dietary stimulation of stem cell production accelerates the organ regeneration in animals. A dietary supplement, Olimpiq StemXCell (Crystal Institute Ltd., Eger, Hungary), containing plant extracts (previously proved to increase the number of circulating CD34(+) cells) was consumed in human equivalent doses by the experimental animals. In the first experiment carbon tetrachloride was applied to CBA/Ca mice, to induce liver damage, and liver weights between StemXCell-fed and control animals were compared 10 days after the treatment. In the second model experimental diabetes was induced in F344 rats by alloxan. Blood sugar levels were measured for 5 weeks in the control and StemXCell-fed groups. The third part of the study investigated the effect of StemXCell on cardiac functions. Eight weeks after causing a myocardial infarction in Wistar rats by isoproterenol, left ventricular ejection fraction was determined as a functional parameter of myocardial regeneration. In all three animal models StemXCell consumption statistically significantly improved the organ regeneration (relative liver weights, 4.78 +/-0.06 g/100 g vs. 4.97 +/- 0.07 g/100 g; blood sugar levels at week 5, 16 +/- 1.30 mmol/L vs. 10.2 +/- 0.92 mmol/L; ejection fraction, 57.5 +/- 2.23 vs. 68.2 +/- 4.94; controls vs. treated animals, respectively). Our study confirms the hypothesis that dietary enhancement of stem cell production may protect against organ injuries and helps in the regeneration.

  13. Secretomes from bone marrow-derived mesenchymal stromal cells enhance periodontal tissue regeneration.

    Kawai, Takamasa; Katagiri, Wataru; Osugi, Masashi; Sugimura, Yukiko; Hibi, Hideharu; Ueda, Minoru

    2015-04-01

    Periodontal tissue regeneration with the use of mesenchymal stromal cells (MSCs) has been regarded as a future cell-based therapy. However, low survival rates and the potential tumorigenicity of implanted MSCs could undermine the efficacy of cell-based therapy. The use of conditioned media from MSCs (MSC-CM) may be a feasible approach to overcome these limitations. The aim of this study was to confirm the effect of MSC-CM on periodontal regeneration. MSC-CM were collected during their cultivation. The concentrations of the growth factors in MSC-CM were measured with the use of enzyme-linked immunoassay. Rat MSCs (rMSCs) and human umbilical vein endothelial cells cultured in MSC-CM were assessed on wound-healing and angiogenesis. The expressions of osteogenetic- and angiogenic-related genes of rMSCs cultured in MSC-CM were quantified by means of real-time reverse transcriptase-polymerase chain reaction analysis. In vivo, periodontal defects were prepared in the rat models and the collagen sponges with MSC-CM were implanted. MSC-CM includes insulin-like growth factor-1, vascular endothelial growth factor, transforming growth factor-β1 and hepatocyte growth factor. In vitro, wound-healing and angiogenesis increased significantly in MSC-CM. The levels of expression of osteogenetic- and angiogenic-related genes were significantly upregulated in rMSCs cultured with MSC-CM. In vivo, in the MSC-CM group, 2 weeks after implantation, immunohistochemical analysis showed several CD31-, CD105-or FLK-1-positive cells occurring frequently. At 4 weeks after implantation, regenerated periodontal tissue was observed in MSC-CM groups. The use of MSC-CM may be an alternative therapy for periodontal tissue regeneration because several cytokines included in MSC-CM will contribute to many processes of complicated periodontal tissue regeneration. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  14. Brain and muscle Arnt-like 1 promotes skeletal muscle regeneration through satellite cell expansion

    Chatterjee, Somik; Yin, Hongshan; Nam, Deokhwa; Li, Yong; Ma, Ke

    2015-01-01

    Circadian clock is an evolutionarily conserved timing mechanism governing diverse biological processes and the skeletal muscle possesses intrinsic functional clocks. Interestingly, although the essential clock transcription activator, Brain and muscle Arnt-like 1 (Bmal1), participates in maintenance of muscle mass, little is known regarding its role in muscle growth and repair. In this report, we investigate the in vivo function of Bmal1 in skeletal muscle regeneration using two muscle injury models. Bmal1 is highly up-regulated by cardiotoxin injury, and its genetic ablation significantly impairs regeneration with markedly suppressed new myofiber formation and attenuated myogenic induction. A similarly defective regenerative response is observed in Bmal1-null mice as compared to wild-type controls upon freeze injury. Lack of satellite cell expansion accounts for the regeneration defect, as Bmal1 −/− mice display significantly lower satellite cell number with nearly abolished induction of the satellite cell marker, Pax7. Furthermore, satellite cell-derived primary myoblasts devoid of Bmal1 display reduced growth and proliferation ex vivo. Collectively, our results demonstrate, for the first time, that Bmal1 is an integral component of the pro-myogenic response that is required for muscle repair. This mechanism may underlie its role in preserving adult muscle mass and could be targeted therapeutically to prevent muscle-wasting diseases. - Highlights: • Bmal1 is highly inducible by muscle injury and myogenic stimuli. • Genetic ablation of Bmal1 significantly impairs muscle regeneration. • Bmal1 promotes satellite cell expansion during muscle regeneration. • Bmal1-deficient primary myoblasts display attenuated growth and proliferation

  15. Enhanced regeneration potential of mobilized dental pulp stem cells from immature teeth.

    Nakayama, H; Iohara, K; Hayashi, Y; Okuwa, Y; Kurita, K; Nakashima, M

    2017-07-01

    We have previously demonstrated that dental pulp stem cells (DPSCs) isolated from mature teeth by granulocyte colony-stimulating factor (G-CSF)-induced mobilization method can enhance angiogenesis/vasculogenesis and improve pulp regeneration when compared with colony-derived DPSCs. However, the efficacy of this method in immature teeth with root-formative stage has never been investigated. Therefore, the aim of this study was to examine the stemness, biological characteristics, and regeneration potential in mobilized DPSCs compared with colony-derived DPSCs from immature teeth. Mobilized DPSCs isolated from immature teeth were compared to colony-derived DPSCs using methods including flow cytometry, migration assays, mRNA expression of angiogenic/neurotrophic factor, and induced differentiation assays. They were also compared in trophic effects of the secretome. Regeneration potential was further compared in an ectopic tooth transplantation model. Mobilized DPSCs had higher migration ability and expressed more angiogenic/neurotrophic factors than DPSCs. The mobilized DPSC secretome produced a higher stimulatory effect on migration, immunomodulation, anti-apoptosis, endothelial differentiation, and neurite extension. In addition, vascularization and pulp regeneration potential were higher in mobilized DPSCs than in DPSCs. G-CSF-induced mobilization method enhances regeneration potential of colony-derived DPSCs from immature teeth. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Mechanosensory organ regeneration in zebrafish depends on a population of multipotent progenitor cells kept latent by Schwann cells.

    Sánchez, Mario; Ceci, Maria Laura; Gutiérrez, Daniela; Anguita-Salinas, Consuelo; Allende, Miguel L

    2016-04-07

    Regenerating damaged tissue is a complex process, requiring progenitor cells that must be stimulated to undergo proliferation, differentiation and, often, migratory behaviors and morphological changes. Multiple cell types, both resident within the damaged tissue and recruited to the lesion site, have been shown to participate. However, the cellular and molecular mechanisms involved in the activation of progenitor cell proliferation and differentiation after injury, and their regulation by different cells types, are not fully understood. The zebrafish lateral line is a suitable system to study regeneration because most of its components are fully restored after damage. The posterior lateral line (PLL) is a mechanosensory system that develops embryonically and is initially composed of seven to eight neuromasts distributed along the trunk and tail, connected by a continuous stripe of interneuromastic cells (INCs). The INCs remain in a quiescent state owing to the presence of underlying Schwann cells. They become activated during development to form intercalary neuromasts. However, no studies have described if INCs can participate in a regenerative event, for example, after the total loss of a neuromast. We used electroablation in transgenic larvae expressing fluorescent proteins in PLL components to completely ablate single neuromasts in larvae and adult fish. This injury results in discontinuity of the INCs, Schwann cells, and the PLL nerve. In vivo imaging showed that the INCs fill the gap left after the injury and can regenerate a new neuromast in the injury zone. Further, a single INC is able to divide and form all cell types in a regenerated neuromast and, during this process, it transiently expresses the sox2 gene, a neural progenitor cell marker. We demonstrate a critical role for Schwann cells as negative regulators of INC proliferation and neuromast regeneration, and that this inhibitory property is completely dependent on active ErbB signaling. The potential

  17. Mitochondrial DNA Unwinding Enzyme Required for Liver Regeneration | Center for Cancer Research

    The liver has an exceptional capacity to proliferate. This ability allows the liver to regenerate its mass after partial surgical removal or injury and is the key to successful partial liver transplants. Liver cells, called hepatocytes, are packed with mitochondria, and regulating mitochondrial DNA (mtDNA) copy number is crucial to mitochondrial function, including energy production, during proliferation. Yves Pommier, M.D., Ph.D., of CCR’s Developmental Therapeutics Branch, and his colleagues recently showed that the vertebrate mitochondrial topoisomerase, Top1mt, was critical in maintaining mitochondrial function in the heart after doxorubicin-induced damage. The group wondered whether Top1mt might play a similar role in liver regeneration.

  18. Biomimetic extracellular matrix mediated somatic stem cell differentiation: applications in dental pulp tissue regeneration

    Ravindran, Sriram; George, Anne

    2015-01-01

    Dental caries is one of the most widely prevalent infectious diseases in the world. It affects more than half of the world's population. The current treatment for necrotic dental pulp tissue arising from dental caries is root canal therapy. This treatment results in loss of tooth sensitivity and vitality making it prone for secondary infections. Over the past decade, several tissue-engineering approaches have attempted regeneration of the dental pulp tissue. Although several studies have highlighted the potential of dental stem cells, none have transitioned into a clinical setting owing to limited availability of dental stem cells and the need for growth factor delivery systems. Our strategy is to utilize the intact ECM of pulp cells to drive lineage specific differentiation of bone marrow derived mesenchymal stem cells. From a clinical perspective, pulp ECM scaffolds can be generated using cell lines and patient specific somatic stem cells can be used for regeneration. Our published results have shown the feasibility of using pulp ECM scaffolds for odontogenic differentiation of non-dental mesenchymal cells. This focused review discusses the issues surrounding dental pulp tissue regeneration and the potential of our strategy to overcome these issues. PMID:25954205

  19. Dental mesenchymal stem cells encapsulated in alginate hydrogel co-delivery microencapsulation system for cartilage regeneration

    Moshaverinia, Alireza; Xu, Xingtian; Chen, Chider; Akiyama, Kentaro; Snead, Malcolm L; Shi, Songtao

    2013-01-01

    Dental-derived MSCs are promising candidates for cartilage regeneration, with high chondrogenic differentiation capacity. This property contributes to making dental MSCs an advantageous therapeutic option compared to current treatment modalities. The MSC delivery vehicle is the principal determinant for the success of MSC-mediated cartilage regeneration therapies. The objectives of this study were to: (1) develop a novel co-delivery system based on TGF-β1 loaded RGD-coupled alginate microspheres encapsulating Periodontal Ligament Stem Cells (PDLSCs) or Gingival Mesenchymal Stem Cells (GMSCs); and (2) investigate dental MSC viability and chondrogenic differentiation in alginate microspheres. The results revealed the sustained release of TGF-β1 from the alginate microspheres. After 4 weeks of chondrogenic differentiation in vitro, PDLSCs, GMSCs as well as human bone marrow mesenchymal stem cells (hBMMSC) (as positive control) revealed chondrogenic gene expression markers (Col II and Sox-9) via qPCR, as well as matrix positively stained by toluidine blue and safranin-O. In animal studies, ectopic cartilage tissue regeneration was observed inside and around the transplanted microspheres, confirmed by histochemical and immunofluorescent staining. Interestingly, PDLSCs showed more chondrogenesis than GMSCs and hBMMSCs (Palginate microencapsulating dental MSCs make a promising candidate for cartilage regeneration. Our results highlight the vital role played by the microenvironment, as well as value of presenting inductive signals for viability and differentiation of MSCs. PMID:23891740

  20. JNK1 induces hedgehog signaling from stellate cells to accelerate liver regeneration in mice.

    Langiewicz, Magda; Graf, Rolf; Humar, Bostjan; Clavien, Pierre A

    2018-04-27

    To improve outcomes of two-staged hepatectomies for large/multiple liver tumors, portal vein ligation (PVL) has been combined with parenchymal transection (coined ALPPS; Associated Liver Partition and Portal vein ligation for Staged hepatectomy) to greatly accelerate liver regeneration. In a novel ALPPS mouse model, we have reported paracrine Indian hedgehog (IHH) signaling from stellate cells as an early contributor to augmented regeneration. Here, we sought to identify upstream regulators of IHH. ALPPS in mice was compared against PVL and additional control surgeries. Potential IHH regulators were identified through in silico mining of transcriptomic data. JNK1 activity was reduced through SP600125 to evaluate its effects on IHH signaling. Recombinant IHH was injected after JNK diminution to substantiate their relationship during accelerated liver regeneration. Mining linked Ihh to Mapk8. JNK1 upregulation after ALPPS was validated and preceded the IHH peak. On immunofluorescence, JNK1 and IHH co-localized in ASMA-positive non-parenchymal cells. Inhibition of JNK1 prior to ALPPS surgery reduced liver weight gain to PVL levels and was accompanied by downregulation of hepatocellular proliferation and the IHH-GLI1-CCND1 axis. In JNK1-inhibited mice, recombinant IHH restored ALPPS-like acceleration of regeneration and re-elevated JNK1 activity, suggesting the presence of a positive IHH-JNK1 feedback loop. JNK1-mediated induction of IHH paracrine signaling from HSCs is essential for accelerated regeneration of parenchymal mass. The JNK1-IHH axis is a mechanism unique to ALPPS surgery and may point to therapeutic alternatives for patients with insufficient regenerative capacity. ALPPS, a novel two-staged hepatectomy, induces an unprecedented acceleration of liver regeneration to enable treatment of unresectable liver tumors. Here, we demonstrate JNK1-IHH signaling as a mechanism underlying the regenerative acceleration induced by ALPPS. Copyright © 2018 European

  1. Activated macrophages create lineage-specific microenvironments for pancreatic acinar- and β-cell regeneration in mice.

    Criscimanna, Angela; Coudriet, Gina M; Gittes, George K; Piganelli, Jon D; Esni, Farzad

    2014-11-01

    Although the cells that contribute to pancreatic regeneration have been widely studied, little is known about the mediators of this process. During tissue regeneration, infiltrating macrophages debride the site of injury and coordinate the repair response. We investigated the role of macrophages in pancreatic regeneration in mice. We used a saporin-conjugated antibody against CD11b to reduce the number of macrophages in mice following diphtheria toxin receptor-mediated cell ablation of pancreatic cells, and evaluated the effects on pancreatic regeneration. We analyzed expression patterns of infiltrating macrophages after cell-specific injury or from the pancreas of nonobese diabetic mice. We developed an in vitro culture system to study the ability of macrophages to induce cell-specific regeneration. Depletion of macrophages impaired pancreatic regeneration. Macrophage polarization, as assessed by expression of tumor necrosis factor-α, interleukin 6, interleukin 10, and CD206, depended on the type of injury. The signals provided by polarized macrophages promoted lineage-specific generation of acinar or endocrine cells. Macrophage from nonobese diabetic mice failed to provide signals necessary for β-cell generation. Macrophages produce cell type-specific signals required for pancreatic regeneration in mice. Additional study of these processes and signals might lead to new approaches for treating type 1 diabetes or pancreatitis. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

  2. Circulating osteogenic cells: implications for injury, repair, and regeneration

    Pignolo, Robert J; Kassem, Moustapha

    2011-01-01

    The aim of this review is to provide a critical reading of recent literature pertaining to the presence of circulating, fluid-phase osteoblastic cells and their possible contribution to bone formation. We have termed this group of cells collectively as circulating osteogenic precursor (COP) cells...

  3. Sonic Hedgehog Initiates Cochlear Hair Cell Regeneration through Downregulation of Retinoblastoma Protein

    Lu, Na; Chen, Yan; Wang, Zhengmin; Chen, Guoling; Lin, Qin; Chen, Zheng-Yi; Li, Huawei

    2013-01-01

    Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1. These results suggest that Shh signaling induces cell cycle re-entry in cochlear sensory epithelium and the production of new hair cells, in part by attenuating pRb function. This study provides an additional route to modulate pRb function with important implications in mammalian hair cell regeneration. PMID:23211596

  4. Ongoing cell death and immune influences on regeneration in the vestibular sensory organs

    Warchol, M. E.; Matsui, J. I.; Simkus, E. L.; Ogilive, J. M.

    2001-01-01

    Hair cells in the vestibular organs of birds have a relatively short life span. Mature hair cells appear to die spontaneously and are then quickly replaced by new hair cells that arise from the division of epithelial supporting cells. A similar regenerative mechanism also results in hair cell replacement after ototoxic damage. The cellular basis of hair cell turnover in the avian ear is not understood. We are investigating the signaling pathways that lead to hair cell death and the relationship between ongoing cell death and cell production. In addition, work from our lab and others has demonstrated that the avian inner ear contains a resident population of macrophages and that enhanced numbers of macrophages are recruited to sites of hair cells lesions. Those observations suggest that macrophages and their secretory products (cytokines) may be involved in hair cell regeneration. Consistent with that suggestion, we have found that treatment with the anti-inflammatory drug dexamethasone reduces regenerative cell proliferation in the avian ear, and that certain macrophage-secreted cytokines can influence the proliferation of vestibular supporting cells and the survival of statoacoustic neurons. Those results suggest a role for the immune system in the process of sensory regeneration in the inner ear.

  5. Immunohistochemical analyses of cell cycle progression and gene expression of biliary epithelial cells during liver regeneration after partial hepatectomy of the mouse.

    Fukuda, Tatsuya; Fukuchi, Tomokazu; Yagi, Shinomi; Shiojiri, Nobuyoshi

    2016-05-20

    The liver has a remarkable regeneration capacity, and, after surgical removal of its mass, the remaining tissue undergoes rapid regeneration through compensatory growth of its constituent cells. Although hepatocytes synchronously proliferate under the control of various signaling molecules from neighboring cells, there have been few detailed analyses on how biliary cells regenerate for their cell population after liver resection. The present study was undertaken to clarify how biliary cells regenerate after partial hepatectomy of mice through extensive analyses of their cell cycle progression and gene expression using immunohistochemical and RT-PCR techniques. When expression of PCNA, Ki67 antigen, topoisomerase IIα and phosphorylated histone H3, which are cell cycle markers, was immunohistochemically examined during liver regeneration, hepatocytes had a peak of the S phase and M phase at 48-72 h after resection. By contrast, biliary epithelial cells had much lower proliferative activity than that of hepatocytes, and their peak of the S phase was delayed. Mitotic figures were rarely detectable in biliary cells. RT-PCR analyses of gene expression of biliary markers such as Spp1 (osteopontin), Epcam and Hnf1b demonstrated that they were upregulated during liver regeneration. Periportal hepatocytes expressed some of biliary markers, including Spp1 mRNA and protein. Some periportal hepatocytes had downregulated expression of HNF4α and HNF1α. Gene expression of Notch signaling molecules responsible for cell fate decision of hepatoblasts to biliary cells during development was upregulated during liver regeneration. Notch signaling may be involved in biliary regeneration.

  6. Hemopoietic precursor cell regeneration following irradiation and syngeneic marrow transplantation

    Melchner, H. von

    1983-01-01

    The transplantation of hemopoietic cells into adequately pretreated recipients represents one of the most promising approaches in the treatment of immunohematological disorders such as aplastic anemia, immunodeficiency diseases, leukemias and malignant lymphomas. The basic property of the hemopoietic cells permitting such therapeutic procedure, namely, the capacity of hemopoietic precursors to actively proliferate and differentiate in recipients suffering the consequences of various kinds of hemopoietic failure, represents the subject of the present review. The main cell populations addressed in the subsequent sections are the hemopoietic precursor cells. Mature end cells and in particular lymphocytes did not receive as much attention.

  7. Kidney stem cells in development, regeneration and cancer.

    Dziedzic, Klaudyna; Pleniceanu, Oren; Dekel, Benjamin

    2014-12-01

    The generation of nephrons during development depends on differentiation via a mesenchymal to epithelial transition (MET) of self-renewing, tissue-specific stem cells confined to a specific anatomic niche of the nephrogenic cortex. These cells may transform to generate oncogenic stem cells and drive pediatric renal cancer. Once nephron epithelia are formed the view of post-MET tissue renal growth and maintenance by adult tissue-specific epithelial stem cells becomes controversial. Recently, genetic lineage tracing that followed clonal evolution of single kidney cells showed that the need for new cells is constantly driven by fate-restricted unipotent clonal expansions in varying kidney segments arguing against a multipotent adult stem cell model. Lineage-restriction was similarly maintained in kidney organoids grown in culture. Importantly, kidney cells in which Wnt was activated were traced to give significant clonal progeny indicating a clonogenic hierarchy. In vivo nephron epithelia may be endowed with the capacity akin to that of unipotent epithelial stem/progenitor such that under specific stimuli can clonally expand/self renew by local proliferation of mature differentiated cells. Finding ways to ex vivo preserve and expand the observed in vivo kidney-forming capacity inherent to both the fetal and adult kidneys is crucial for taking renal regenerative medicine forward. Some of the strategies used to achieve this are sorting human fetal nephron stem/progenitor cells, growing adult nephrospheres or reprogramming differentiated kidney cells toward expandable renal progenitors. Copyright © 2014. Published by Elsevier Ltd.

  8. Stem cell technology using bioceramics: hard tissue regeneration towards clinical application

    Hiroe Ohnishi, Yasuaki Oda and Hajime Ohgushi

    2010-01-01

    Full Text Available Mesenchymal stem cells (MSCs are adult stem cells which show differentiation capabilities toward various cell lineages. We have already used MSCs for treatments of osteoarthritis, bone necrosis and bone tumor. For this purpose, culture expanded MSCs were combined with various ceramics and then implanted. Because of rejection response to allogeneic MSC implantation, we have utilized patients' own MSCs for the treatment. Bone marrow is a good cell source of MSCs, although the MSCs also exist in adipose tissue. When comparing osteogenic differentiation of these MSCs, bone marrow MSCs show more extensive bone forming capability than adipose MSCs. Thus, the bone marrow MSCs are useful for bone tissue regeneration. However, the MSCs show limited proliferation and differentiation capabilities that hindered clinical applications in some cases. Recent advances reveal that transduction of plural transcription factors into human adult cells results in generation of new type of stem cells called induced pluripotent stem cells (iPS cells. A drawback of the iPS cells for clinical applications is tumor formation after their in vivo implantation; therefore it is difficult to use iPS cells for the treatment. To circumvent the problem, we transduced a single factor of either SOX2 or NANOG into the MSCs and found high proliferation as well as osteogenic differentiation capabilities of the MSCs. The stem cells could be combined with bioceramics for clinical applications. Here, we summarize our recent technologies using adult stem cells in viewpoints of bone tissue regeneration.

  9. TOPICAL REVIEW: Stem cell technology using bioceramics: hard tissue regeneration towards clinical application

    Ohnishi, Hiroe; Oda, Yasuaki; Ohgushi, Hajime

    2010-02-01

    Mesenchymal stem cells (MSCs) are adult stem cells which show differentiation capabilities toward various cell lineages. We have already used MSCs for treatments of osteoarthritis, bone necrosis and bone tumor. For this purpose, culture expanded MSCs were combined with various ceramics and then implanted. Because of rejection response to allogeneic MSC implantation, we have utilized patients' own MSCs for the treatment. Bone marrow is a good cell source of MSCs, although the MSCs also exist in adipose tissue. When comparing osteogenic differentiation of these MSCs, bone marrow MSCs show more extensive bone forming capability than adipose MSCs. Thus, the bone marrow MSCs are useful for bone tissue regeneration. However, the MSCs show limited proliferation and differentiation capabilities that hindered clinical applications in some cases. Recent advances reveal that transduction of plural transcription factors into human adult cells results in generation of new type of stem cells called induced pluripotent stem cells (iPS cells). A drawback of the iPS cells for clinical applications is tumor formation after their in vivo implantation; therefore it is difficult to use iPS cells for the treatment. To circumvent the problem, we transduced a single factor of either SOX2 or NANOG into the MSCs and found high proliferation as well as osteogenic differentiation capabilities of the MSCs. The stem cells could be combined with bioceramics for clinical applications. Here, we summarize our recent technologies using adult stem cells in viewpoints of bone tissue regeneration.

  10. The blastema and epimorphic regeneration in mammals.

    Seifert, Ashley W; Muneoka, Ken

    2018-01-15

    Studying regeneration in animals where and when it occurs is inherently interesting and a challenging research topic within developmental biology. Historically, vertebrate regeneration has been investigated in animals that display enhanced regenerative abilities and we have learned much from studying organ regeneration in amphibians and fish. From an applied perspective, while regeneration biologists will undoubtedly continue to study poikilothermic animals (i.e., amphibians and fish), studies focused on homeotherms (i.e., mammals and birds) are also necessary to advance regeneration biology. Emerging mammalian models of epimorphic regeneration are poised to help link regenerative biology and regenerative medicine. The regenerating rodent digit tip, which parallels human fingertip regeneration, and the regeneration of large circular defects through the ear pinna in spiny mice and rabbits, provide tractable, experimental systems where complex tissue structures are regrown through blastema formation and morphogenesis. Using these models as examples, we detail similarities and differences between the mammalian blastema and its classical counterpart to arrive at a broad working definition of a vertebrate regeneration blastema. This comparison leads us to conclude that regenerative failure is not related to the availability of regeneration-competent progenitor cells, but is most likely a function of the cellular response to the microenvironment that forms following traumatic injury. Recent studies demonstrating that targeted modification of this microenvironment can restrict or enhance regenerative capabilities in mammals helps provide a roadmap for eventually pushing the limits of human regeneration. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Acceleration of Regeneration of Large-Gap Peripheral Nerve Injuries Using Acellular Nerve Allografts plus amniotic Fluid Derived Stem Cells (AFS)

    2017-09-01

    cells (AFS) to promote and accelerate nerve regeneration . The presence of the AFS will provide support for the regenerating axons without the...plus AFS cells . Cross sections of the distal part of the regenerated nerves were evaluated by light and electronic microscopy. ANA plus AFS group...and myelin thickness in ANA plus AFS cells treated group (Figure 2.1.1), indicating enhanced regenerating ability of the axons. Neuromuscular

  12. Activated STAT5 Confers Resistance to Intestinal Injury by Increasing Intestinal Stem Cell Proliferation and Regeneration

    Shila Gilbert

    2015-02-01

    Full Text Available Intestinal epithelial stem cells (IESCs control the intestinal homeostatic response to inflammation and regeneration. The underlying mechanisms are unclear. Cytokine-STAT5 signaling regulates intestinal epithelial homeostasis and responses to injury. We link STAT5 signaling to IESC replenishment upon injury by depletion or activation of Stat5 transcription factor. We found that depletion of Stat5 led to deregulation of IESC marker expression and decreased LGR5+ IESC proliferation. STAT5-deficient mice exhibited worse intestinal histology and impaired crypt regeneration after γ-irradiation. We generated a transgenic mouse model with inducible expression of constitutively active Stat5. In contrast to Stat5 depletion, activation of STAT5 increased IESC proliferation, accelerated crypt regeneration, and conferred resistance to intestinal injury. Furthermore, ectopic activation of STAT5 in mouse or human stem cells promoted LGR5+ IESC self-renewal. Accordingly, STAT5 promotes IESC proliferation and regeneration to mitigate intestinal inflammation. STAT5 is a functional therapeutic target to improve the IESC regenerative response to gut injury.

  13. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2 mediated regeneration of sinusoidal endothelial cells

    Hooper, Andrea T.; Butler, Jason M.; Nolan, Daniel J; Kranz, Andrea; Iida, Kaoruko; Kobayashi, Mariko; Kopp, Hans-Georg; Shido, Koji; Petit, Isabelle; Yanger, Kilangsungla; James, Daylon; Witte, Larry; Zhu, Zhenping; Wu, Yan; Pytowski, Bronislaw; Rosenwaks, Zev; Mittal, Vivek; Sato, Thomas N.; Rafii, Shahin

    2011-01-01

    SUMMARY The phenotypic attributes and molecular determinants for the regeneration of bone marrow (BM) sinusoidal endothelial cells (SECs) and their contribution to hematopoiesis are unknown. We show that after myelosuppression VEGFR2 activation promotes reassembly of regressed SECs, reconstituting hematopoietic stem and progenitor cells (HSPCs). VEGFR2 and VEGFR3 expression are restricted to BM vasculature, demarcating a continuous network of VEGFR2+VEGFR3+Sca1− SECs and VEGFR2+VEGFR3−Sca1+ arterioles. While chemotherapy (5FU) and sublethal irradiation (650 rad) induce minor SEC regression, lethal irradiation (950 rad) induces severe regression of SECs requiring BM transplantation (BMT) for regeneration. Conditional deletion of VEGFR2 in adult mice blocks regeneration of SECs in sublethally irradiated animals, preventing hematopoietic reconstitution. Inhibition of VEGFR2 signaling in lethally irradiated wild type mice rescued with BMT severely impairs SEC reconstruction, preventing engraftment and reconstitution of HSPCs. Therefore, activation of VEGFR2 is critical for regeneration of VEGFR3+Sca1− SECs that are essential for engraftment and restoration of HSPCs and hematopoiesis. PMID:19265665

  14. Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration

    Saclier, Marielle; Yacoub-Youssef, Houda; Mackey, Abigail

    2013-01-01

    , we explored both in vitro and in vivo, in human, the interactions of differentially activated MPs with myogenic precursor cells (MPCs) during adult myogenesis and skeletal muscle regeneration. We showed in vitro that through the differential secretion of cytokines and growth factors, proinflammatory...... anti-inflammatory markers. These data demonstrate for the first time in human that MPs sequentially orchestrate adult myogenesis during regeneration of damaged skeletal muscle. These results support the emerging concept that inflammation, through MP activation, controls stem cell fate and coordinates......Macrophages (MPs) exert either beneficial or deleterious effects on tissue repair, depending on their activation/polarization state. They are crucial for adult skeletal muscle repair, notably by acting on myogenic precursor cells. However, these interactions have not been fully characterized. Here...

  15. Investigation of cell adhesion in chitosan membranes for peripheral nerve regeneration

    Carvalho, Cristiana R.; López-Cebral, Rita; Silva-Correia, Joana; Silva, Joana M.; Mano, João F.; Silva, Tiago H. [3B' s Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark – Parque de Ciência e Tecnologia, 4805-017, Barco, Guimarães (Portugal); ICVS/3B' s - PT Government Associate Laboratory, Braga, Guimarães (Portugal); Freier, Thomas [MEDOVENT GmbH, Friedrich-Koenig-Str. 3, D-55129 Mainz (Germany); Reis, Rui L. [3B' s Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark – Parque de Ciência e Tecnologia, 4805-017, Barco, Guimarães (Portugal); ICVS/3B' s - PT Government Associate Laboratory, Braga, Guimarães (Portugal); Oliveira, Joaquim M., E-mail: miguel.oliveira@dep.uminho.pt [3B' s Research Group - Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark – Parque de Ciência e Tecnologia, 4805-017, Barco, Guimarães (Portugal); ICVS/3B' s - PT Government Associate Laboratory, Braga, Guimarães (Portugal)

    2017-02-01

    Peripheral nerve injuries have produced major concerns in regenerative medicine for several years, as the recovery of normal nerve function continues to be a significant clinical challenge. Chitosan (CHT), because of its good biocompatibility, biodegradability and physicochemical properties, has been widely used as a biomaterial in tissue engineering scaffolding. In this study, CHT membranes were produced with three different Degrees of Acetylation (DA), envisioning its application in peripheral nerve regeneration. The three CHT membranes (DA I: 1%, DA II: 2%, DA III: 5%) were extensively characterized and were found to have a smooth and flat surface, with DA III membrane having slightly higher roughness and surface energy. All the membranes presented suitable mechanical properties and did not show any signs of calcification after SBF test. Biodegradability was similar for all samples, and adequate to physically support neurite outgrowth. The in vitro cell culture results indicate selective cell adhesion. The CHT membranes favoured Schwann cells invasion and proliferation, with a display of appropriate cytoskeletal morphology. At the same time they presented low fibroblast infiltration. This fact may be greatly beneficial for the prevention of fibrotic tissue formation, a common phenomenon impairing peripheral nerve regeneration. The great deal of results obtained during this work permitted to select the formulation with the greatest potential for further biological tests. - Highlights: • Three chitosan membranes were produced with very specific degrees of acetylation (DA I: 1%, DA II: 2%, DA III: 5%). • Physicochemical characterization of the membranes showed their suitability for peripheral nerve regeneration purposes. • In vitro cellular tests confirmed the potential of the membranes as peripheral nerve regeneration systems. • The results indicated that DA III membrane should be the one considered for further peripheral nerve regeneration studies.

  16. Investigation of cell adhesion in chitosan membranes for peripheral nerve regeneration

    Carvalho, Cristiana R.; López-Cebral, Rita; Silva-Correia, Joana; Silva, Joana M.; Mano, João F.; Silva, Tiago H.; Freier, Thomas; Reis, Rui L.; Oliveira, Joaquim M.

    2017-01-01

    Peripheral nerve injuries have produced major concerns in regenerative medicine for several years, as the recovery of normal nerve function continues to be a significant clinical challenge. Chitosan (CHT), because of its good biocompatibility, biodegradability and physicochemical properties, has been widely used as a biomaterial in tissue engineering scaffolding. In this study, CHT membranes were produced with three different Degrees of Acetylation (DA), envisioning its application in peripheral nerve regeneration. The three CHT membranes (DA I: 1%, DA II: 2%, DA III: 5%) were extensively characterized and were found to have a smooth and flat surface, with DA III membrane having slightly higher roughness and surface energy. All the membranes presented suitable mechanical properties and did not show any signs of calcification after SBF test. Biodegradability was similar for all samples, and adequate to physically support neurite outgrowth. The in vitro cell culture results indicate selective cell adhesion. The CHT membranes favoured Schwann cells invasion and proliferation, with a display of appropriate cytoskeletal morphology. At the same time they presented low fibroblast infiltration. This fact may be greatly beneficial for the prevention of fibrotic tissue formation, a common phenomenon impairing peripheral nerve regeneration. The great deal of results obtained during this work permitted to select the formulation with the greatest potential for further biological tests. - Highlights: • Three chitosan membranes were produced with very specific degrees of acetylation (DA I: 1%, DA II: 2%, DA III: 5%). • Physicochemical characterization of the membranes showed their suitability for peripheral nerve regeneration purposes. • In vitro cellular tests confirmed the potential of the membranes as peripheral nerve regeneration systems. • The results indicated that DA III membrane should be the one considered for further peripheral nerve regeneration studies.

  17. Post-irradiation regeneration of early B-lymphocyte precursor cells in mouse bone marrow

    Park, Y.-H.; Osmond, D.G.

    1989-01-01

    To examine the sequential development of early B-cell precursors in mouse bone marrow, B-lineage cells have been examined during a wave of post-irradiation regeneration. Cell phenotypes have been defined for (i) terminal deoxynucleotidyl transferase (TdT); (ii) B220 glycoprotein, (iii) μ heavy chains in the cytoplasm (cμ) and at the cell surface (sμ). Three populations of μ - cells (TdT + 14.8 - ; TdT + 14.8 + ; TdT - 14.8 + ) have been proposed to be early B-cell precursors which would give rise to cμ + sμ - pre-B cells and to sμ + B lymphocytes. The timing, cell-size shifts and progressive amplification of the waves of regeneration accord with a dynamic model in which the TdT + 14.8 - , TdT + 14.8 + and TdT - 14.8 + cells form three successive stages in B-cell differentiation before the expression of μ chains, presumptively including the stage of μ chain gene rearrangement. In addition, the results provide an experimental system for the enrichment of early B-cell precursors in mouse bone marrow. (author)

  18. Collective cell migration in morphogenesis, regeneration and cancer.

    Friedl, P.H.A.; Gilmour, D.

    2009-01-01

    The collective migration of cells as a cohesive group is a hallmark of the tissue remodelling events that underlie embryonic morphogenesis, wound repair and cancer invasion. In such migration, cells move as sheets, strands, clusters or ducts rather than individually, and use similar actin- and

  19. MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration

    Mokalled, Mayssa H.; Johnson, Aaron N.; Creemers, Esther E.; Olson, Eric N.

    2012-01-01

    In response to skeletal muscle injury, satellite cells, which function as a myogenic stem cell population, become activated, expand through proliferation, and ultimately fuse with each other and with damaged myofibers to promote muscle regeneration. Here, we show that members of the Myocardin family of transcriptional coactivators, MASTR and MRTF-A, are up-regulated in satellite cells in response to skeletal muscle injury and muscular dystrophy. Global and satellite cell-specific deletion of MASTR in mice impairs skeletal muscle regeneration. This impairment is substantially greater when MRTF-A is also deleted and is due to aberrant differentiation and excessive proliferation of satellite cells. These abnormalities mimic those associated with genetic deletion of MyoD, a master regulator of myogenesis, which is down-regulated in the absence of MASTR and MRTF-A. Consistent with an essential role of MASTR in transcriptional regulation of MyoD expression, MASTR activates a muscle-specific postnatal MyoD enhancer through associations with MEF2 and members of the Myocardin family. Our results provide new insights into the genetic circuitry of muscle regeneration and identify MASTR as a central regulator of this process. PMID:22279050

  20. miR-378 attenuates muscle regeneration by delaying satellite cell activation and differentiation in mice.

    Zeng, Ping; Han, Wanhong; Li, Changyin; Li, Hu; Zhu, Dahai; Zhang, Yong; Liu, Xiaohong

    2016-09-01

    Skeletal muscle mass and homeostasis during postnatal muscle development and regeneration largely depend on adult muscle stem cells (satellite cells). We recently showed that global overexpression of miR-378 significantly reduced skeletal muscle mass in mice. In the current study, we used miR-378 transgenic (Tg) mice to assess the in vivo functional effects of miR-378 on skeletal muscle growth and regeneration. Cross-sectional analysis of skeletal muscle tissues showed that the number and size of myofibers were significantly lower in miR-378 Tg mice than in wild-type mice. Attenuated cardiotoxin-induced muscle regeneration in miR-378 Tg mice was found to be associated with delayed satellite cell activation and differentiation. Mechanistically, miR-378 was found to directly target Igf1r in muscle cells both in vitro and in vivo These miR-378 Tg mice may provide a model for investigating the physiological and pathological roles of skeletal muscle in muscle-associated diseases in humans, particularly in sarcopenia. © The Author 2016. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  1. Promising Therapeutic Strategies for Mesenchymal Stem Cell-Based Cardiovascular Regeneration: From Cell Priming to Tissue Engineering

    Seung Taek Ji

    2017-01-01

    Full Text Available The primary cause of death among chronic diseases worldwide is ischemic cardiovascular diseases, such as stroke and myocardial infarction. Recent evidence indicates that adult stem cell therapies involving cardiovascular regeneration represent promising strategies to treat cardiovascular diseases. Owing to their immunomodulatory properties and vascular repair capabilities, mesenchymal stem cells (MSCs are strong candidate therapeutic stem cells for use in cardiovascular regeneration. However, major limitations must be overcome, including their very low survival rate in ischemic lesion. Various attempts have been made to improve the poor survival and longevity of engrafted MSCs. In order to develop novel therapeutic strategies, it is necessary to first identify stem cell modulators for intracellular signal triggering or niche activation. One promising therapeutic strategy is the priming of therapeutic MSCs with stem cell modulators before transplantation. Another is a tissue engineering-based therapeutic strategy involving a cell scaffold, a cell-protein-scaffold architecture made of biomaterials such as ECM or hydrogel, and cell patch- and 3D printing-based tissue engineering. This review focuses on the current clinical applications of MSCs for treating cardiovascular diseases and highlights several therapeutic strategies for promoting the therapeutic efficacy of MSCs in vitro or in vivo from cell priming to tissue engineering strategies, for use in cardiovascular regeneration.

  2. Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion

    Santoni-Rugiu, Eric; Jelnes, Peter; Thorgeirsson, Snorri S

    2005-01-01

    created in the liver by a certain insult. This review will focus on molecular responses controlling activation and expansion of the hepatic progenitor cell niche, emphasizing similarities and differences in the microenvironments orchestrating regeneration by recruitment of progenitor cell populations...... cells, and recruited inflammatory cells as well as the variety of growth-modulating molecules produced and/or harboured by these elements. The cellular and molecular responses to different regenerative stimuli seem to depend on the injury inflicted and consequently on the molecular microenvironment...

  3. Cartilage regeneration by chondrogenic induced adult stem cells in osteoarthritic sheep model.

    Ude, Chinedu C; Sulaiman, Shamsul B; Min-Hwei, Ng; Hui-Cheng, Chen; Ahmad, Johan; Yahaya, Norhamdan M; Saim, Aminuddin B; Idrus, Ruszymah B H

    2014-01-01

    In this study, Adipose stem cells (ADSC) and bone marrow stem cells (BMSC), multipotent adult cells with the potentials for cartilage regenerations were induced to chondrogenic lineage and used for cartilage regenerations in surgically induced osteoarthritis in sheep model. Osteoarthritis was induced at the right knee of sheep by complete resection of the anterior cruciate ligament and medial meniscus following a 3-weeks exercise regimen. Stem cells from experimental sheep were culture expanded and induced to chondrogenic lineage. Test sheep received a single dose of 2 × 10(7) autologous PKH26-labelled, chondrogenically induced ADSCs or BMSCs as 5 mls injection, while controls received 5 mls culture medium. The proliferation rate of ADSCs 34.4 ± 1.6 hr was significantly higher than that of the BMSCs 48.8 ± 5.3 hr (P = 0.008). Chondrogenic induced BMSCs had significantly higher expressions of chondrogenic specific genes (Collagen II, SOX9 and Aggrecan) compared to chondrogenic ADSCs (P = 0.031, 0.010 and 0.013). Grossly, the treated knee joints showed regenerated de novo cartilages within 6 weeks post-treatment. On the International Cartilage Repair Society grade scores, chondrogenically induced ADSCs and BMSCs groups had significantly lower scores than controls (P = 0.0001 and 0.0001). Fluorescence of the tracking dye (PKH26) in the injected cells showed that they had populated the damaged area of cartilage. Histological staining revealed loosely packed matrixes of de novo cartilages and immunostaining demonstrated the presence of cartilage specific proteins, Collagen II and SOX9. Autologous chondrogenically induced ADSCs and BMSCs could be promising cell sources for cartilage regeneration in osteoarthritis.

  4. Cartilage regeneration by chondrogenic induced adult stem cells in osteoarthritic sheep model.

    Chinedu C Ude

    Full Text Available OBJECTIVES: In this study, Adipose stem cells (ADSC and bone marrow stem cells (BMSC, multipotent adult cells with the potentials for cartilage regenerations were induced to chondrogenic lineage and used for cartilage regenerations in surgically induced osteoarthritis in sheep model. METHODS: Osteoarthritis was induced at the right knee of sheep by complete resection of the anterior cruciate ligament and medial meniscus following a 3-weeks exercise regimen. Stem cells from experimental sheep were culture expanded and induced to chondrogenic lineage. Test sheep received a single dose of 2 × 10(7 autologous PKH26-labelled, chondrogenically induced ADSCs or BMSCs as 5 mls injection, while controls received 5 mls culture medium. RESULTS: The proliferation rate of ADSCs 34.4 ± 1.6 hr was significantly higher than that of the BMSCs 48.8 ± 5.3 hr (P = 0.008. Chondrogenic induced BMSCs had significantly higher expressions of chondrogenic specific genes (Collagen II, SOX9 and Aggrecan compared to chondrogenic ADSCs (P = 0.031, 0.010 and 0.013. Grossly, the treated knee joints showed regenerated de novo cartilages within 6 weeks post-treatment. On the International Cartilage Repair Society grade scores, chondrogenically induced ADSCs and BMSCs groups had significantly lower scores than controls (P = 0.0001 and 0.0001. Fluorescence of the tracking dye (PKH26 in the injected cells showed that they had populated the damaged area of cartilage. Histological staining revealed loosely packed matrixes of de novo cartilages and immunostaining demonstrated the presence of cartilage specific proteins, Collagen II and SOX9. CONCLUSION: Autologous chondrogenically induced ADSCs and BMSCs could be promising cell sources for cartilage regeneration in osteoarthritis.

  5. Concise review: bridging the gap: bone regeneration using skeletal stem cell-based strategies-where are we now?

    Dawson, Jonathan I; Kanczler, Janos; Kassem, Moustapha

    2014-01-01

    Skeletal stem cells confer to bone its innate capacity for regeneration and repair. Bone regeneration strategies seek to harness and enhance this regenerative capacity for the replacement of tissue damaged or lost through congenital defects, trauma, functional/esthetic problems, and a broad range...... for musculoskeletal regeneration. Stem Cells 2014;32:35-44...... of diseases associated with an increasingly aged population. This review describes the state of the field and current steps to translate and apply skeletal stem cell biology in the clinic and the problems therein. Challenges are described along with key strategies including the isolation and ex vivo expansion...

  6. Periodontal regeneration in swine after cell injection and cell sheet transplantation of human dental pulp stem cells following good manufacturing practice.

    Hu, Jingchao; Cao, Yu; Xie, Yilin; Wang, Hua; Fan, Zhipeng; Wang, Jinsong; Zhang, Chunmei; Wang, Jinsong; Wu, Chu-Tse; Wang, Songlin

    2016-09-09

    Periodontitis, one of the most prevalent infectious diseases in humans, results in the destruction of tooth-supporting tissues. The purpose of the present study is to evaluate the effect of cell injection and cell sheet transplantation on periodontal regeneration in a swine model. In the present study, human dental pulp stem cells (hDPSCs) were transplanted into a swine model for periodontal regeneration. Twelve miniature pigs were used to generate periodontitis with bone defects of 5 mm in width, 7 mm in length, and 3 mm in depth. hDPSCs were obtained for bone regeneration using cell injection or cell sheet transplantation. After 12 weeks, clinical, radiological, and histological assessments of regenerated periodontal tissues were performed to compare periodontal regeneration treated with xenogeneic cell injection and cell sheet implantation. Our study showed that translating hDPSCs into this large animal model could significantly improve periodontal bone regeneration and soft tissue healing. After 12 weeks, both the hDPSC sheet treatment and hDPSC injection significantly improved periodontal tissue healing clinically in comparison with the control group. The volume of regenerative bone in the hDPSC sheet group (52.7 ± 4.1 mm(3)) was significantly larger than in the hDPSC injection group (32.4 ± 5.1 mm(3)) (P cell sheet transplantation significantly regenerated periodontal bone in swine. The hDPSC sheet had more bone regeneration capacity compared with hDPSC injection.

  7. Pathologic bladder microenvironment attenuates smooth muscle differentiation of skin derived precursor cells: implications for tissue regeneration.

    Cornelia Tolg

    Full Text Available Smooth muscle cell containing organs (bladder, heart, blood vessels are damaged by a variety of pathological conditions necessitating surgery or organ replacement. Currently, regeneration of contractile tissues is hampered by lack of functional smooth muscle cells. Multipotent skin derived progenitor cells (SKPs can easily be isolated from adult skin and can be differentiated in vitro into contractile smooth muscle cells by exposure to FBS. Here we demonstrate an inhibitory effect of a pathologic contractile organ microenvironment on smooth muscle cell differentiation of SKPs. In vivo, urinary bladder strain induces microenvironmental changes leading to de-differentiation of fully differentiated bladder smooth muscle cells. Co-culture of SKPs with organoids isolated from ex vivo stretched bladders or exposure of SKPs to diffusible factors released by stretched bladders (e.g. bFGF suppresses expression of smooth muscle markers (alpha SMactin, calponin, myocardin, myosin heavy chain as demonstrated by qPCR and immunofluorescent staining. Rapamycin, an inhibitor of mTOR signalling, previously observed to prevent bladder strain induced de-differentiation of fully differentiated smooth muscle cells in vitro, inhibits FBS-induced smooth muscle cell differentiation of undifferentiated SKPs. These results suggest that intended precursor cell differentiation may be paradoxically suppressed by the disease context for which regeneration may be required. Organ-specific microenvironment contexts, particularly prevailing disease, may play a significant role in modulating or attenuating an intended stem cell phenotypic fate, possibly explaining the variable and inefficient differentiation of stem cell constructs in in vivo settings. These observations must be considered in drafting any regeneration strategies.

  8. Drosophila Wnt and STAT Define Apoptosis-Resistant Epithelial Cells for Tissue Regeneration after Irradiation.

    Shilpi Verghese

    2016-09-01

    Full Text Available Drosophila melanogaster larvae irradiated with doses of ionizing radiation (IR that kill about half of the cells in larval imaginal discs still develop into viable adults. How surviving cells compensate for IR-induced cell death to produce organs of normal size and appearance remains an active area of investigation. We have identified a subpopulation of cells within the continuous epithelium of Drosophila larval wing discs that shows intrinsic resistance to IR- and drug-induced apoptosis. These cells reside in domains of high Wingless (Wg, Drosophila Wnt-1 and STAT92E (sole Drosophila signal transducer and activator of transcription [STAT] homolog activity and would normally form the hinge in the adult fly. Resistance to IR-induced apoptosis requires STAT and Wg and is mediated by transcriptional repression of the pro-apoptotic gene reaper. Lineage tracing experiments show that, following irradiation, apoptosis-resistant cells lose their identity and translocate to areas of the wing disc that suffered abundant cell death. Our findings provide a new paradigm for regeneration in which it is unnecessary to invoke special damage-resistant cell types such as stem cells. Instead, differences in gene expression within a population of genetically identical epithelial cells can create a subpopulation with greater resistance, which, following damage, survive, alter their fate, and help regenerate the tissue.

  9. Streptomycin ototoxicity and hair cell regeneration in the adult pigeon utricle

    Frank, T. C.; Dye, B. J.; Newlands, S. D.; Dickman, J. D.

    1999-01-01

    OBJECTIVE: The purpose of this study was to develop a technique to investigate the regeneration of utricular hair cells in the adult pigeon (Columba livia) following complete hair cell loss through administration of streptomycin. STUDY DESIGN: Experimental animal study. METHODS: Animals were divided into four groups. Group 1 received 10 to 15 days of systemic streptomycin injections. Animals in Groups 2 and 3 received a single direct placement of a 1-, 2-, 4-, or 8-mg streptomycin dose into the perilymphatic space. Animals in Groups 1 and 2 were analyzed within 1 week from injection to investigate hair cell destruction, whereas Group 3 was investigated at later dates to study hair cell recovery. Group 4 animals received a control injection of saline into the perilymphatic space. Damage and recovery were quantified by counting hair cells in isolated utricles using scanning electron microscopy. RESULTS: Although systemic injections failed to reliably achieve complete utricular hair cell destruction, a single direct placement of a 2-, 4-, or 8-mg streptomycin dose caused complete destruction within the first week. Incomplete hair cell loss was observed with the 1-mg dose. Over the long term, regeneration of the hair cells was seen with the 2-mg dose but not the 8-mg dose. Control injections of saline into the perilymphatic space caused no measurable hair cell loss. CONCLUSIONS: Direct placement of streptomycin into the perilymph is an effective, reliable method for complete destruction of utricular hair cells while preserving the regenerative potential of the neuroepithelium.

  10. Influence of bone marrow-derived mesenchymal stem cells pre-implantation differentiation approach on periodontal regeneration in vivo.

    Cai, Xinjie; Yang, Fang; Yan, Xiangzhen; Yang, Wanxun; Yu, Na; Oortgiesen, Daniel A W; Wang, Yining; Jansen, John A; Walboomers, X Frank

    2015-04-01

    The implantation of bone marrow-derived mesenchymal stem cells (MSCs) has previously been shown successful to achieve periodontal regeneration. However, the preferred pre-implantation differentiation strategy (e.g. maintenance of stemness, osteogenic or chondrogenic induction) to obtain optimal periodontal regeneration is still unknown. This in vivo study explored which differentiation approach is most suitable for periodontal regeneration. Mesenchymal stem cells were obtained from Fischer rats and seeded onto poly(lactic-co-glycolic acid)/poly(ɛ-caprolactone) electrospun scaffolds, and then pre-cultured under different in vitro conditions: (i) retention of multilineage differentiation potential; (ii) osteogenic differentiation approach; and (iii) chondrogenic differentiation approach. Subsequently, the cell-scaffold constructs were implanted into experimental periodontal defects of Fischer rats, with empty scaffolds as controls. After 6 weeks of implantation, histomorphometrical analyses were applied to evaluate the regenerated periodontal tissues. The chondrogenic differentiation approach showed regeneration of alveolar bone and ligament tissues. The retention of multilineage differentiation potential supported only ligament regeneration, while the osteogenic differentiation approach boosted alveolar bone regeneration. Chondrogenic differentiation of MSCs before implantation is a useful strategy for regeneration of alveolar bone and periodontal ligament, in the currently used rat model. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Efficient Computational Design of a Scaffold for Cartilage Cell Regeneration

    Tajsoleiman, Tannaz; Jafar Abdekhodaie, Mohammad; Gernaey, Krist V.

    2018-01-01

    Due to the sensitivity of mammalian cell cultures, understanding the influence of operating conditions during a tissue generation procedure is crucial. In this regard, a detailed study of scaffold based cell culture under a perfusion flow is presented with the aid of mathematical modelling...... and computational fluid dynamics (CFD). With respect to the complexity of the case study, this work focuses solely on the effect of nutrient and metabolite concentrations, and the possible influence of fluid-induced shear stress on a targeted cell (cartilage) culture. The simulation set up gives the possibility...... of predicting the cell culture behavior under various operating conditions and scaffold designs. Thereby, the exploitation of the predictive simulation into a newly developed stochastic routine provides the opportunity of exploring improved scaffold geometry designs. This approach was applied on a common type...

  12. Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle.

    Slattery, Eric L; Speck, Judith D; Warchol, Mark E

    2009-09-01

    The sensory hair cells of the cochlea and vestibular organs are essential for normal hearing and balance function. The mammalian ear possesses a very limited ability to regenerate hair cells and their loss can lead to permanent sensory impairment. In contrast, hair cells in the avian ear are quickly regenerated after acoustic trauma or ototoxic injury. The very different regenerative abilities of the avian vs. mammalian ear can be attributed to differences in injury-evoked expression of genes that either promote or inhibit the production of new hair cells. Gene expression is regulated both by the binding of cis-regulatory molecules to promoter regions as well as through structural modifications of chromatin (e.g., methylation and acetylation). This study examined effects of histone deacetylases (HDACs), whose main function is to modify histone acetylation, on the regulation of regenerative proliferation in the chick utricle. Cultures of regenerating utricles and dissociated cells from the utricular sensory epithelia were treated with the HDAC inhibitors valproic acid, trichostatin A, sodium butyrate, and MS-275. All of these molecules prevent the enzymatic removal of acetyl groups from histones, thus maintaining nuclear chromatin in a "relaxed" (open) configuration. Treatment with all inhibitors resulted in comparable decreases in supporting cell proliferation. We also observed that treatment with the HDAC1-, 2-, and 3-specific inhibitor MS-275 was sufficient to reduce proliferation and that two class I HDACs--HDAC1 and HDAC2--were expressed in the sensory epithelium of the utricle. These results suggest that inhibition of specific type I HDACs is sufficient to prevent cell cycle entry in supporting cells. Notably, treatment with HDAC inhibitors did not affect the differentiation of replacement hair cells. We conclude that histone deacetylation is a positive regulator of regenerative proliferation but is not critical for avian hair cell differentiation.

  13. In vitro study of stem cell communication via gap junctions for fibrocartilage regeneration at entheses.

    Nayak, Bibhukalyan Prasad; Goh, James Cho Hong; Toh, Siew Lok; Satpathy, Gyan Ranjan

    2010-03-01

    Entheses are fibrocartilaginous organs that bridge ligament with bone at their interface and add significant insertional strength. To replace a severely damaged ligament, a tissue-engineered graft preinstalled with interfacial fibrocartilage, which is being regenerated from stem cells, appears to be more promising than ligament-alone graft. Such a concept can be realized by a biomimetic approach of establishing a dynamic communication of stem cells with bone cells and/or ligament fibroblasts in vitro. The current study has two objectives. The first objective is to demonstrate functional coculture of bone marrow-derived stem cells (BMSCs) with mature bone cells/ligament fibroblasts as evidenced by gap-junctional communication in vitro. The second objective is to investigate the role of BMSCs in the regeneration of fibrocartilage within the coculture. Rabbit bone/ligament fibroblasts were dual-stained with DiI-Red and calcein (gap-junction permeable dye), and cocultured with unlabeled BMSCs at fixed ratio (1:10). The functional gap junction was demonstrated by the transfer of calcein from donor to recipient cells that was confirmed and quantified by flow cytometry. Type 2 collagen (cartilage extracellular matrix-specific protein) expressed by the mixed cell lines in the cocultures were estimated by real-time reverse transcription PCR and compared with that of the ligament-bone coculture (control). Significant transfer of calcein into BMSCs was observed and flow cytometry analyses showed a gradual increase in the percentage of BMSCs acquiring calcein with time. Cocultures that included BMSCs expressed significantly more type 2 collagen compared with the control. The current study, for the first time, reported the expression of gap-junctional communication of BMSCs with two adherent cell lines of musculoskeletal system in vitro and also confirmed that incorporation of stem cells augments fibrocartilage regeneration. The results open up a path to envisage a composite

  14. Progenitor potential of nkx6.1-expressing cells throughout zebrafish life and during beta cell regeneration.

    Ghaye, Aurélie P; Bergemann, David; Tarifeño-Saldivia, Estefania; Flasse, Lydie C; Von Berg, Virginie; Peers, Bernard; Voz, Marianne L; Manfroid, Isabelle

    2015-09-02

    In contrast to mammals, the zebrafish has the remarkable capacity to regenerate its pancreatic beta cells very efficiently. Understanding the mechanisms of regeneration in the zebrafish and the differences with mammals will be fundamental to discovering molecules able to stimulate the regeneration process in mammals. To identify the pancreatic cells able to give rise to new beta cells in the zebrafish, we generated new transgenic lines allowing the tracing of multipotent pancreatic progenitors and endocrine precursors. Using novel bacterial artificial chromosome transgenic nkx6.1 and ascl1b reporter lines, we established that nkx6.1-positive cells give rise to all the pancreatic cell types and ascl1b-positive cells give rise to all the endocrine cell types in the zebrafish embryo. These two genes are initially co-expressed in the pancreatic primordium and their domains segregate, not as a result of mutual repression, but through the opposite effects of Notch signaling, maintaining nkx6.1 expression while repressing ascl1b in progenitors. In the adult zebrafish, nkx6.1 expression persists exclusively in the ductal tree at the tip of which its expression coincides with Notch active signaling in centroacinar/terminal end duct cells. Tracing these cells reveals that they are able to differentiate into other ductal cells and into insulin-expressing cells in normal (non-diabetic) animals. This capacity of ductal cells to generate endocrine cells is supported by the detection of ascl1b in the nkx6.1:GFP ductal cell transcriptome. This transcriptome also reveals, besides actors of the Notch and Wnt pathways, several novel markers such as id2a. Finally, we show that beta cell ablation in the adult zebrafish triggers proliferation of ductal cells and their differentiation into insulin-expressing cells. We have shown that, in the zebrafish embryo, nkx6.1+ cells are bona fide multipotent pancreatic progenitors, while ascl1b+ cells represent committed endocrine precursors. In

  15. Peripheral Nerve Injuries and Transplantation of Olfactory Ensheathing Cells for Axonal Regeneration and Remyelination: Fact or Fiction?

    Christine Radtke

    2012-10-01

    Full Text Available Successful nerve regeneration after nerve trauma is not only important for the restoration of motor and sensory functions, but also to reduce the potential for abnormal sensory impulse generation that can occur following neuroma formation. Satisfying functional results after severe lesions are difficult to achieve and the development of interventional methods to achieve optimal functional recovery after peripheral nerve injury is of increasing clinical interest. Olfactory ensheathing cells (OECs have been used to improve axonal regeneration and functional outcome in a number of studies in spinal cord injury models. The rationale is that the OECs may provide trophic support and a permissive environment for axonal regeneration. The experimental transplantation of OECs to support and enhance peripheral nerve regeneration is much more limited. This chapter reviews studies using OECs as an experimental cell therapy to improve peripheral nerve regeneration.

  16. Use of rat mature adipocyte-derived dedifferentiated fat cells as a cell source for periodontal tissue regeneration

    Daisuke eAkita

    2016-02-01

    Full Text Available Lipid-free fibroblast-like cells, known as dedifferentiated fat (DFAT cells, can be generated from mature adipocytes with a large single lipid droplet. DFAT cells can re-establish their active proliferation ability and can transdifferentiate into various cell types under appropriate culture conditions. The first objective of this study was to compare the multilineage differentiation potential of DFAT cells with that of adipose-derived stem cells (ASCs on mesenchymal stem cellsWe obtained DFAT cells and ASCs from inbred rats and found that rat DFAT cells possess higher osteogenic differentiation potential than rat ASCs. On the other hand, DFAT cells show similar adipogenic differentiation, and chondrogenic differentiation potential in comparison with ASCs. The second objective of this study was to assess the regenerative potential of DFAT cells combined with novel solid scaffolds composed of PLGA (Poly d, l-lactic-co-glycolic acid on periodontal tissue, and to compare this with the regenerative potential of ASCs combined with PLGA scaffolds. Cultured DFAT cells and ASCs were seeded onto PLGA scaffolds (DFAT/PLGA and ASCs/PLGA and transplanted into periodontal fenestration defects in rat mandible. Micro computed tomography analysis revealed a significantly higher amount of bone regeneration in the DFAT/PLGA group compared with that of ASCs/PLGA and PLGA-alone groups at 2, 3 and 5 weeks after transplantation. Similarly, histomorphometric analysis showed that DFAT/PLGA groups had significantly greater width of cementum, periodontal ligament and alveolar bone than ASCs/PLGA and PLGA-alone groups. In addition, transplanted fluorescent-labeled DFAT cells were observed in the periodontal ligament beside the newly formed bone and cementum. These findings suggest that DFAT cells have a greater potential for enhancing periodontal tissue regeneration than ASCs. Therefore, DFAT cells are a promising cell source for periodontium regeneration.

  17. Muscle satellite cells are functionally impaired in myasthenia gravis: consequences on muscle regeneration.

    Attia, Mohamed; Maurer, Marie; Robinet, Marieke; Le Grand, Fabien; Fadel, Elie; Le Panse, Rozen; Butler-Browne, Gillian; Berrih-Aknin, Sonia

    2017-12-01

    Myasthenia gravis (MG) is a neuromuscular disease caused in most cases by anti-acetyl-choline receptor (AChR) autoantibodies that impair neuromuscular signal transmission and affect skeletal muscle homeostasis. Myogenesis is carried out by muscle stem cells called satellite cells (SCs). However, myogenesis in MG had never been explored. The aim of this study was to characterise the functional properties of myasthenic SCs as well as their abilities in muscle regeneration. SCs were isolated from muscle biopsies of MG patients and age-matched controls. We first showed that the number of Pax7+ SCs was increased in muscle sections from MG and its experimental autoimmune myasthenia gravis (EAMG) mouse model. Myoblasts isolated from MG muscles proliferate and differentiate more actively than myoblasts from control muscles. MyoD and MyoG were expressed at a higher level in MG myoblasts as well as in MG muscle biopsies compared to controls. We found that treatment of control myoblasts with MG sera or monoclonal anti-AChR antibodies increased the differentiation and MyoG mRNA expression compared to control sera. To investigate the functional ability of SCs from MG muscle to regenerate, we induced muscle regeneration using acute cardiotoxin injury in the EAMG mouse model. We observed a delay in maturation evidenced by a decrease in fibre size and MyoG mRNA expression as well as an increase in fibre number and embryonic myosin heavy-chain mRNA expression. These findings demonstrate for the first time the altered function of SCs from MG compared to control muscles. These alterations could be due to the anti-AChR antibodies via the modulation of myogenic markers resulting in muscle regeneration impairment. In conclusion, the autoimmune attack in MG appears to have unsuspected pathogenic effects on SCs and muscle regeneration, with potential consequences on myogenic signalling pathways, and subsequently on clinical outcome, especially in the case of muscle stress.

  18. Stem cells in skin regeneration: biomaterials and computational models

    Daniele eTartarini

    2016-01-01

    Full Text Available The increased incidence of diabetes and tumors, associated with global demographic issues (aging and life styles, has pointed out the importance to develop new strategies for the effective management of skin wounds. Individuals affected by these diseases are in fact highly exposed to the risk of delayed healing of the injured tissue that typically leads to a pathological inflammatory state and consequently to chronic wounds. Therapies based on stem cells have been proposed for the treatment of these wounds, thanks to the ability of stem cells to self-renew and specifically differentiate in response to the target bimolecular environment. Here we discuss how advanced biomedical devices can be developed by combining stem cells with properly engineered biomaterials and computational models. Examples include composite skin substitutes and bioactive dressings with controlled porosity and surface topography for controlling the infiltration and differentiation of the cells. In this scenario, mathematical frameworks for the simulation of cell population growth can provide support for the design of bio-constructs, reducing the need of expensive, time-consuming and ethically controversial animal experimentation.

  19. A Short-Term Exposure to Tributyltin Blocks Leydig Cell Regeneration in the Adult Rat Testis

    Xiaolong Wu

    2017-10-01

    Full Text Available Background: Tributyltin (TBT is widely used as an antifouling agent that may cause reproductive toxicity. The mechanism of TBT on Leydig cell development is still unknown. The objective of the present study was to investigate whether a brief exposure to low doses of TBT permanently affects Leydig cell development and to clarify the underlying mechanism.Methods: Adult male Sprague Dawley rats were randomly assigned into four groups and gavaged normal saline (control, 0.1, 1.0, or 10.0 mg/kg/day TBT for a consecutive 10 days, respectively. At the end of TBT treatment, all rats received a single intraperitoneal injection of 75 mg/kg ethane dimethane sulfonate (EDS to eliminate all of adult Leydig cells. Leydig cells began a developmental regeneration process on post-EDS day 35. The Leydig cell regeneration was evaluated by measuring serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels on post-EDS day 7, 35, and 56, the expression levels of Leydig cell genes, Leydig cell morphology and number and proliferation on post-EDS day 56.Results: TBT significantly reduced serum testosterone levels on post-EDS day 35 and 56 and increased serum luteinizing hormone and follicle-stimulating hormone levels on post-EDS day 56 at ≥1 mg/kg/day. Immunohistochemical staining showed that there were fewer regenerated Leydig cells in the TBT-treated testis on post-EDS day 56. Further study demonstrated that the mRNA or protein levels of Leydig (Lhcgr, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd17b3 and Sertoli cells (Fshr, Dhh, and Sox9 were significantly down-regulated in the TBT-treated testes when compared to the control. Immunofluorescent staining showed that TBT inhibited Leydig cell proliferation as judged by the reduced number of proliferating cyclin nuclear antigen-positive Leydig cells on post-EDS day 35.Conclusion: The present study demonstrated that a short-term TBT exposure blocked Leydig cell developmental regeneration process via down

  20. A Short-Term Exposure to Tributyltin Blocks Leydig Cell Regeneration in the Adult Rat Testis.

    Wu, Xiaolong; Liu, Jianpeng; Duan, Yue; Gao, Shiyu; Lü, Yao; Li, Xiaoheng; Zhu, Qiqi; Chen, Xianwu; Lin, Jing; Ye, Leping; Ge, Ren-Shan

    2017-01-01

    Background: Tributyltin (TBT) is widely used as an antifouling agent that may cause reproductive toxicity. The mechanism of TBT on Leydig cell development is still unknown. The objective of the present study was to investigate whether a brief exposure to low doses of TBT permanently affects Leydig cell development and to clarify the underlying mechanism. Methods: Adult male Sprague Dawley rats were randomly assigned into four groups and gavaged normal saline (control), 0.1, 1.0, or 10.0 mg/kg/day TBT for a consecutive 10 days, respectively. At the end of TBT treatment, all rats received a single intraperitoneal injection of 75 mg/kg ethane dimethane sulfonate (EDS) to eliminate all of adult Leydig cells. Leydig cells began a developmental regeneration process on post-EDS day 35. The Leydig cell regeneration was evaluated by measuring serum testosterone, luteinizing hormone, and follicle-stimulating hormone levels on post-EDS day 7, 35, and 56, the expression levels of Leydig cell genes, Leydig cell morphology and number and proliferation on post-EDS day 56. Results: TBT significantly reduced serum testosterone levels on post-EDS day 35 and 56 and increased serum luteinizing hormone and follicle-stimulating hormone levels on post-EDS day 56 at ≥1 mg/kg/day. Immunohistochemical staining showed that there were fewer regenerated Leydig cells in the TBT-treated testis on post-EDS day 56. Further study demonstrated that the mRNA or protein levels of Leydig ( Lhcgr , Cyp11a1, Hsd3b1, Cyp17a1 , and Hsd17b3 ) and Sertoli cells ( Fshr , Dhh , and Sox9 ) were significantly down-regulated in the TBT-treated testes when compared to the control. Immunofluorescent staining showed that TBT inhibited Leydig cell proliferation as judged by the reduced number of proliferating cyclin nuclear antigen-positive Leydig cells on post-EDS day 35. Conclusion: The present study demonstrated that a short-term TBT exposure blocked Leydig cell developmental regeneration process via down

  1. Mechanical Stretching Promotes Skin Tissue Regeneration via Enhancing Mesenchymal Stem Cell Homing and Transdifferentiation.

    Liang, Xiao; Huang, Xiaolu; Zhou, Yiwen; Jin, Rui; Li, Qingfeng

    2016-07-01

    Skin tissue expansion is a clinical procedure for skin regeneration to reconstruct cutaneous defects that can be accompanied by severe complications. The transplantation of mesenchymal stem cells (MSCs) has been proven effective in promoting skin expansion and helping to ameliorate complications; however, systematic understanding of its mechanism remains unclear. MSCs from luciferase-Tg Lewis rats were intravenously transplanted into a rat tissue expansion model to identify homing and transdifferentiation. To clarify underlying mechanisms, a systematic approach was used to identify the differentially expressed genes between mechanically stretched human MSCs and controls. The biological significance of these changes was analyzed through bioinformatic methods. We further investigated genes and pathways of interest to disclose their potential role in mechanical stretching-induced skin regeneration. Cross sections of skin samples from the expanded group showed significantly more luciferase(+) and stromal cell-derived factor 1α (SDF-1α)(+), luciferase(+)keratin 14(+), and luciferase(+)CD31(+) cells than the control group, indicating MSC transdifferentiation into epidermal basal cells and endothelial cells after SDF-1α-mediated homing. Microarray analysis suggested upregulation of genes related to hypoxia, vascularization, and cell proliferation in the stretched human MSCs. Further investigation showed that the homing of MSCs was blocked by short interfering RNA targeted against matrix metalloproteinase 2, and that mechanical stretching-induced vascular endothelial growth factor A upregulation was related to the Janus kinase/signal transducer and activator of transcription (Jak-STAT) and Wnt signaling pathways. This study determines that mechanical stretching might promote skin regeneration by upregulating MSC expression of genes related to hypoxia, vascularization, and cell proliferation; enhancing transplanted MSC homing to the expanded skin; and

  2. Understanding positional cues in salamander limb regeneration: implications for optimizing cell-based regenerative therapies

    Catherine D. McCusker

    2014-06-01

    Full Text Available Regenerative medicine has reached the point where we are performing clinical trials with stem-cell-derived cell populations in an effort to treat numerous human pathologies. However, many of these efforts have been challenged by the inability of the engrafted populations to properly integrate into the host environment to make a functional biological unit. It is apparent that we must understand the basic biology of tissue integration in order to apply these principles to the development of regenerative therapies in humans. Studying tissue integration in model organisms, where the process of integration between the newly regenerated tissues and the ‘old’ existing structures can be observed and manipulated, can provide valuable insights. Embryonic and adult cells have a memory of their original position, and this positional information can modify surrounding tissues and drive the formation of new structures. In this Review, we discuss the positional interactions that control the ability of grafted cells to integrate into existing tissues during the process of salamander limb regeneration, and discuss how these insights could explain the integration defects observed in current cell-based regenerative therapies. Additionally, we describe potential molecular tools that can be used to manipulate the positional information in grafted cell populations, and to promote the communication of positional cues in the host environment to facilitate the integration of engrafted cells. Lastly, we explain how studying positional information in current cell-based therapies and in regenerating limbs could provide key insights to improve the integration of cell-based regenerative therapies in the future.

  3. Stem cell secretome-rich nanoclay hydrogel: a dual action therapy for cardiovascular regeneration

    Waters, Renae; Pacelli, Settimio; Maloney, Ryan; Medhi, Indrani; Ahmed, Rafeeq P. H.; Paul, Arghya

    2016-03-01

    A nanocomposite hydrogel with photocrosslinkable micro-porous networks and a nanoclay component was successfully prepared to control the release of growth factor-rich stem cell secretome. The proven pro-angiogenic and cardioprotective potential of this new bioactive system provides a valuable therapeutic platform for cardiac tissue repair and regeneration.A nanocomposite hydrogel with photocrosslinkable micro-porous networks and a nanoclay component was successfully prepared to control the release of growth factor-rich stem cell secretome. The proven pro-angiogenic and cardioprotective potential of this new bioactive system provides a valuable therapeutic platform for cardiac tissue repair and regeneration. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr07806g

  4. Enhanced periodontal tissue regeneration by periodontal cell implantation

    Yu, N.; Oortgiesen, D.A.W.; Bronckers, A.L.J.J.; Yang, F.; Walboomers, X.F.; Jansen, J.A.

    2013-01-01

    Aim Due to a lack of regenerative potential, current treatments for periodontal defects do not always provide satisfactory clinical results. Previously, the implantation of a biomaterial scaffold-cell construct has been suggested as a clinically achievable approach. In this study, it was aimed to

  5. Regeneration of Tissues and Organs Using Autologous Cells

    Anthony Atala, M D

    2012-10-11

    The proposed work aims to address three major challenges to the field of regenerative medicine: 1) the growth and expansion of regenerative cells outside the body in controlled in vitro environments, 2) supportive vascular supply for large tissue engineered constructs, and 3) interactive biomaterials that can orchestrate tissue development in vivo. Toward this goal, we have engaged a team of scientists with expertise in cell and molecular biology, physiology, biomaterials, controlled release, nanomaterials, tissue engineering, bioengineering, and clinical medicine to address all three challenges. This combination of resources, combined with the vast infrastructure of the WFIRM, have brought to bear on projects to discover and test new sources of autologous cells that can be used therapeutically, novel methods to improve vascular support for engineered tissues in vivo, and to develop intelligent biomaterials and bioreactor systems that interact favorably with stem and progenitor cells to drive tissue maturation. The Institute's ongoing programs are aimed at developing regenerative medicine technologies that employ a patient's own cells to help restore or replace tissue and organ function. This DOE program has provided a means to solve some of the vexing problems that are germane to many tissue engineering applications, regardless of tissue type or target disease. By providing new methods that are the underpinning of tissue engineering, this program facilitated advances that can be applied to conditions including heart disease, diabetes, renal failure, nerve damage, vascular disease, and cancer, to name a few. These types of conditions affect millions of Americans at a cost of more than $400 billion annually. Regenerative medicine holds the promise of harnessing the body's own power to heal itself. By addressing the fundamental challenges of this field in a comprehensive and focused fashion, this DOE program has opened new opportunities to treat

  6. Rac1 selective activation improves retina ganglion cell survival and regeneration.

    Erika Lorenzetto

    Full Text Available In adult mammals, after optic nerve injury, retinal ganglion cells (RGCs do not regenerate their axons and most of them die by apoptosis within a few days. Recently, several strategies that activate neuronal intracellular pathways were proposed to prevent such degenerative processes. The rho-related small GTPase Rac1 is part of a complex, still not fully understood, intracellular signaling network, mediating in neurons many effects, including axon growth and cell survival. However, its role in neuronal survival and regeneration in vivo has not yet been properly investigated. To address this point we intravitreally injected selective cell-penetrating Rac1 mutants after optic nerve crush and studied the effect on RGC survival and axonal regeneration. We injected two well-characterized L61 constitutively active Tat-Rac1 fusion protein mutants, in which a second F37A or Y40C mutation confers selectivity in downstream signaling pathways. Results showed that, 15 days after crush, both mutants were able to improve survival and to prevent dendrite degeneration, while the one harboring the F37A mutation also improved axonal regeneration. The treatment with F37A mutant for one month did not improve the axonal elongation respect to 15 days. Furthermore, we found an increase of Pak1 T212 phosphorylation and ERK1/2 expression in RGCs after F37A treatment, whereas ERK1/2 was more activated in glial cells after Y40C administration. Our data suggest that the selective activation of distinct Rac1-dependent pathways could represent a therapeutic strategy to counteract neuronal degenerative processes in the retina.

  7. Chitosan derived co-spheroids of neural stem cells and mesenchymal stem cells for neural regeneration.

    Han, Hao-Wei; Hsu, Shan-Hui

    2017-10-01

    Chitosan has been considered as candidate biomaterials for neural applications. The effective treatment of neurodegeneration or injury to the central nervous system (CNS) is still in lack nowadays. Adult neural stem cells (NSCs) represents a promising cell source to treat the CNS diseases but they are limited in number. Here, we developed the core-shell spheroids of NSCs (shell) and mesenchymal stem cells (MSCs, core) by co-culturing cells on the chitosan surface. The NSCs in chitosan derived co-spheroids displayed a higher survival rate than those in NSC homo-spheroids. The direct interaction of NSCs with MSCs in the co-spheroids increased the Notch activity and differentiation tendency of NSCs. Meanwhile, the differentiation potential of MSCs in chitosan derived co-spheroids was significantly enhanced toward neural lineages. Furthermore, NSC homo-spheroids and NSC/MSC co-spheroids derived on chitosan were evaluated for their in vivo efficacy by the embryonic and adult zebrafish brain injury models. The locomotion activity of zebrafish receiving chitosan derived NSC homo-spheroids or NSC/MSC co-spheroids was partially rescued in both models. Meanwhile, the higher survival rate was observed in the group of adult zebrafish implanted with chitosan derived NSC/MSC co-spheroids as compared to NSC homo-spheroids. These evidences indicate that chitosan may provide an extracellular matrix-like environment to drive the interaction and the morphological assembly between NSCs and MSCs and promote their neural differentiation capacities, which can be used for neural regeneration. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Stem Cells in Skin Regeneration, Wound Healing, and Their Clinical Applications.

    Ojeh, Nkemcho; Pastar, Irena; Tomic-Canic, Marjana; Stojadinovic, Olivera

    2015-10-23

    The skin is the largest organ of the body and has an array of functions. Skin compartments, epidermis, and hair follicles house stem cells that are indispensable for skin homeostasis and regeneration. These stem cells also contribute to wound repair, resulting in restoration of tissue integrity and function of damaged tissue. Unsuccessful wound healing processes often lead to non-healing wounds. Chronic wounds are caused by depletion of stem cells and a variety of other cellular and molecular mechanisms, many of which are still poorly understood. Current chronic wound therapies are limited, so the search to develop better therapeutic strategies is ongoing. Adult stem cells are gaining recognition as potential candidates for numerous skin pathologies. In this review, we will discuss epidermal and other stem cells present in the skin, and highlight some of the therapeutic applications of epidermal stem cells and other adult stem cells as tools for cell/scaffold-based therapies for non-healing wounds and other skin disorders. We will also discuss emerging concepts and offer some perspectives on how skin tissue-engineered products can be optimized to provide efficacious therapy in cutaneous repair and regeneration.

  9. Morphogenetic Mechanisms in the Cyclic Regeneration of Hair Follicles and Deer Antlers from Stem Cells

    Li, Chunyi; McMahon, Chris

    2013-01-01

    We have made comparisons between hair follicles (HFs) and antler units (AUs)—two seemingly unrelated mammalian organs. HFs are tiny and concealed within skin, whereas AUs are gigantic and grown externally for visual display. However, these two organs share some striking similarities. Both consist of permanent and cyclic/temporary components and undergo stem-cell-based organogenesis and cyclic regeneration. Stem cells of both organs reside in the permanent part and the growth centres are located in the temporary part of each respective organ. Organogenesis and regeneration of both organs depend on epithelial-mesenchymal interactions. Establishment of these interactions requires stem cells and reactive/niche cells (dermal papilla cells for HFs and epidermal cells for AUs) to be juxtaposed, which is achieved through destruction of the cyclic part to bring the reactive cells into close proximity to the respective stem cell niche. Developments of HFs and AUs are regulated by similar endocrine (particularly testosterone) and paracrine (particularly IGF1) factors. Interestingly, these two organs come to interplay during antlerogenesis. In conclusion, we believe that investigators from the fields of both HF and AU biology could greatly benefit from a comprehensive comparison between these two organs. PMID:24383056

  10. Auto-regeneration of mice testicle seminiferous tubules due to malnutrition based on stem cells mobilization using honey

    Erma Safitri

    2016-03-01

    Conclusions: Results of this study revealed a significantly different of C34 and CD45 expressions between groups, also an increase SSCs expression and testicle seminiferous tubules cells regeneration as well.

  11. Comparative retention of fission fragment 147Pm in regenerated and fetal liver on induction of chromosome aberrations in these cells

    Zhu Shoupeng; Zheng Siying; Wang Liuyi; Yang Shujin

    1989-01-01

    The purpose of the present study is to ascertain comparative retention of fission fragment 147 Pm in regenerated and fetal liver on induction of chromosome aberrations in these cells. The results indicated that retention of 147 Pm in regenerated liver was about 700 times than in fetal liver. The cumulative absorption dose in regenerated liver was about 2.87 Gy, while in fetal liver-only 0.004 Gy. Under the same conditions, the incidence rate of chromosome aberrations in regenerated liver cells induced by 147 Pm was 50.2%, and in fetal liver cells-about 28.3%. It should be concluded that the radiosensitivity to 147 Pm was not uniform among the regenerated and fetal liver cells. The study suggested that fetal liver cells show to be more radiosensitive to 147 Pm than regenerated liver cells. Among the type of aberrations in both cells induced by 147 Pm, chromatid breakages were predominant, accompanied with a few chromosome breakages

  12. Novel Adult Stem Cells for Peripheral Nerve Regeneration

    2013-09-01

    presentations related to this project o Days of Molecular Medicine-Regenerative Medicine, Hong Kong . 11/2011 Figure 4. Differentiation of MVSCs into...School, Boston. 10/2012 o Distinguished Seminar Series, Mechanical and Industrial Engineering, University of Toronto, Canada. 11/2012 o International...10% of the cells in the carotid arterial tunica media of SM-MHC-Cre/LoxP- EGFP mice were not labelled with EGFP, indicating the existence of a small

  13. Three-Dimensional Bioprinting Nanotechnologies towards Clinical Application of Stem Cells and Their Secretome in Salivary Gland Regeneration

    Joao N. Ferreira

    2016-01-01

    Full Text Available Salivary gland (SG functional damage and severe dry mouth (or xerostomia are commonly observed in a wide range of medical conditions from autoimmune to metabolic disorders as well as after radiotherapy to treat specific head and neck cancers. No effective therapy has been developed to completely restore the SG functional damage on the long-term and reverse the poor quality of life of xerostomia patients. Cell- and secretome-based strategies are currently being tested in vitro and in vivo for the repair and/or regeneration of the damaged SG using (1 epithelial SG stem/progenitor cells from salispheres or explant cultures as well as (2 nonepithelial stem cell types and/or their bioactive secretome. These strategies will be the focus of our review. Herein, innovative 3D bioprinting nanotechnologies for the generation of organotypic cultures and SG organoids/mini-glands will also be discussed. These bioprinting technologies will allow researchers to analyze the secretome components and extracellular matrix production, as well as their biofunctional effects in 3D mini-glands ex vivo. Improving our understanding of the SG secretome is critical to develop effective secretome-based therapies towards the regeneration and/or repair of all SG compartments for proper restoration of saliva secretion and flow into the oral cavity.

  14. Endothelial progenitor cells regenerate infracted myocardium with neovascularisation development.

    Abd El Aziz, M T; Abd El Nabi, E A; Abd El Hamid, M; Sabry, D; Atta, H M; Rahed, L A; Shamaa, A; Mahfouz, S; Taha, F M; Elrefaay, S; Gharib, D M; Elsetohy, Khaled A

    2015-03-01

    We achieved possibility of isolation, characterization human umbilical cord blood endothelial progenitor cells (EPCs), examination potency of EPCs to form new blood vessels and differentiation into cardiomyoctes in canines with acute myocardial infarction (AMI). EPCs were separated and cultured from umbilical cord blood. Their phenotypes were confirmed by uptake of double stains dioctadecyl tetramethylindocarbocyanine-labeled acetylated LDL and FITC-labeled Ulex europaeus agglutinin 1 (DILDL-UEA-1). EPCs of cord blood were counted. Human VEGFR-2 and eNOS from the cultured EPCs were assessed by qPCR. Human EPCs was transplanted intramyocardially in canines with AMI. ECG and cardiac enzymes (CK-MB and Troponin I) were measured to assess severity of cellular damage. Histopathology was done to assess neovascularisation. Immunostaining was done to detect EPCs transdifferentiation into cardiomyocytes in peri-infarct cardiac tissue. qPCR for human genes (hVEGFR-2, and eNOS) was done to assess homing and angiogenic function of transplanted EPCs. Cultured human cord blood exhibited an increased number of EPCs and significant high expression of hVEGFR-2 and eNOS genes in the culture cells. Histopathology showed increased neovascularization and immunostaining showed presence of EPCs newly differentiated into cardiomyocyte-like cells. Our findings suggested that hEPCs can mediate angiogenesis and differentiate into cardiomyoctes in canines with AMI.

  15. Endothelial progenitor cells regenerate infracted myocardium with neovascularisation development

    M.T. Abd El Aziz

    2015-03-01

    Full Text Available We achieved possibility of isolation, characterization human umbilical cord blood endothelial progenitor cells (EPCs, examination potency of EPCs to form new blood vessels and differentiation into cardiomyoctes in canines with acute myocardial infarction (AMI. EPCs were separated and cultured from umbilical cord blood. Their phenotypes were confirmed by uptake of double stains dioctadecyl tetramethylindocarbocyanine-labeled acetylated LDL and FITC-labeled Ulex europaeus agglutinin 1 (DILDL-UEA-1. EPCs of cord blood were counted. Human VEGFR-2 and eNOS from the cultured EPCs were assessed by qPCR. Human EPCs was transplanted intramyocardially in canines with AMI. ECG and cardiac enzymes (CK-MB and Troponin I were measured to assess severity of cellular damage. Histopathology was done to assess neovascularisation. Immunostaining was done to detect EPCs transdifferentiation into cardiomyocytes in peri-infarct cardiac tissue. qPCR for human genes (hVEGFR-2, and eNOS was done to assess homing and angiogenic function of transplanted EPCs. Cultured human cord blood exhibited an increased number of EPCs and significant high expression of hVEGFR-2 and eNOS genes in the culture cells. Histopathology showed increased neovascularization and immunostaining showed presence of EPCs newly differentiated into cardiomyocyte-like cells. Our findings suggested that hEPCs can mediate angiogenesis and differentiate into cardiomyoctes in canines with AMI.

  16. Stem cell property of postmigratory cranial neural crest cells and their utility in alveolar bone regeneration and tooth development.

    Chung, Il-Hyuk; Yamaza, Takayoshi; Zhao, Hu; Choung, Pill-Hoon; Shi, Songtao; Chai, Yang

    2009-04-01

    The vertebrate neural crest is a multipotent cell population that gives rise to a variety of different cell types. We have discovered that postmigratory cranial neural crest cells (CNCCs) maintain mesenchymal stem cell characteristics and show potential utility for the regeneration of craniofacial structures. We are able to induce the osteogenic differentiation of postmigratory CNCCs, and this differentiation is regulated by bone morphogenetic protein (BMP) and transforming growth factor-beta signaling pathways. After transplantation into a host animal, postmigratory CNCCs form bone matrix. CNCC-formed bones are distinct from bones regenerated by bone marrow mesenchymal stem cells. In addition, CNCCs support tooth germ survival via BMP signaling in our CNCC-tooth germ cotransplantation system. Thus, we conclude that postmigratory CNCCs preserve stem cell features, contribute to craniofacial bone formation, and play a fundamental role in supporting tooth organ development. These findings reveal a novel function for postmigratory CNCCs in organ development, and demonstrate the utility of these CNCCs in regenerating craniofacial structures.

  17. Potential of stem cell based therapy and tissue engineering in the regeneration of the central nervous system

    An Yihua; Tsang, Kent K S; Zhang Han

    2006-01-01

    The insufficiency of self-repair and regeneration of the central nervous system (CNS) leads to difficulty of rehabilitation of the injured brain. In the past few decades, the significant progress in cell therapy and tissue engineering has contributed to the functional recovery of the CNS to a great extent. The present review focuses on the potential role of stem cell based therapy and tissue engineering in the regeneration of the CNS. (topical review)

  18. The combination use of platelet-rich fibrin and treated dentin matrix for tooth root regeneration by cell homing.

    Ji, Baohui; Sheng, Lei; Chen, Gang; Guo, Shujuan; Xie, Li; Yang, Bo; Guo, Weihua; Tian, Weidong

    2015-01-01

    Endogenous regeneration through cell homing provides an alternative approach for tissue regeneration, except cell transplantation, especially considering clinical translation. However, tooth root regeneration through cell homing remains a provocative approach in need of intensive study. Both platelet-rich fibrin (PRF) and treated dentin matrix (TDM) are warehouses of various growth factors, which can promote cell homing. We hypothesized that endogenous stem cells are able to sense biological cues from PRF membrane and TDM, and contribute to the regeneration of tooth root, including soft and hard periodontal tissues. Therefore, the biological effects of canine PRF and TDM on periodontal ligament stem cells (PDLSCs) and bone marrow mesenchymal stem cells (BMSCs) were evaluated respectively in vitro. Beagle dogs were used as orthotopic transplantation model. It was found that PRF significantly recruited and stimulated the proliferation of PDLSCs and BMSCs in vitro. Together, PRF and TDM induced cell differentiation by upregulating the mineralization-related gene expression of bone sialoprotein (BSP) and osteopotin (OPN) after 7 days coculture. In vivo, transplantation of autologous PRF and allogeneic TDM into fresh tooth extraction socket achieved successful root regeneration 3 months postsurgery, characterized by the regeneration of cementum and periodontal ligament (PDL)-like tissues with orientated fibers, indicative of functional restoration. The results suggest that tooth root connected to the alveolar bone by cementum-PDL complex can be regenerated through the implantation of PRF and TDM in a tooth socket microenvironment, probably by homing of BMSCs and PDLSCs. Furthermore, bioactive cues and inductive microenvironment are key factors for endogenous regeneration. This approach provides a tangible pathway toward clinical translation.

  19. Regeneration of CO poisoned PEM fuel cells by periodic pulsed oxidation

    Adams, W.A.; Blair, J.; Bullock, K.R.; Gardner, C.L.

    2004-01-01

    CO poisoning is a major issue when reformate is used as a fuel in PEM fuel cells. Normally it is necessary to reduce the CO to very low levels (∼5 ppm) and CO tolerant catalysts, such as Pt-Ru, are often employed. As an alternative approach, we have studied the use of pulsed oxidation for the regeneration of CO poisoned cells. Results are presented for the regeneration of Pt and Pt-Ru anodes in a PEM fuel cell fed with CO concentrations as high as 10,000 ppm. The results show periodic removal of CO from the catalyst surface by pulsed oxidation can increase the average cell potential and increase overall efficiency. A method for enhancing the performance of a fuel cell stack using a microprocessor-based Fuel Cell Health Manager (FCHM) has been developed. The results of a cost/benefit analysis for the use of a FCHM on a 4 kW residential fuel cell system are presented. (author)

  20. Impaired liver regeneration is associated with reduced cyclin B1 in natural killer T cell-deficient mice.

    Ben Ya'acov, Ami; Meir, Hadar; Zolotaryova, Lydia; Ilan, Yaron; Shteyer, Eyal

    2017-03-23

    It has been shown that the proportion of natural killer T cells is markedly elevated during liver regeneration and their activation under different conditions can modulate this process. As natural killer T cells and liver injury are central in liver regeneration, elucidating their role is important. The aim of the current study is to explore the role of natural killer T cells in impaired liver regeneration. Concanvalin A was injected 4 days before partial hepatectomy to natural killer T cells- deficient mice or to anti CD1d1-treated mice. Ki-67 and proliferating cell nuclear antigen were used to measure hepatocytes proliferation. Expression of hepatic cyclin B1 and proliferating cell nuclear antigen were evaluated by Western Blot and liver injury was assessed by ALT and histology. Natural killer T cells- deficient or mice injected with anti CD1d antibodies exhibited reduced liver regeneration. These mice were considerably resistant to ConA-induced liver injury. In the absence of NKT cells hepatic proliferating cell nuclear antigen and cyclin B1 decreased in mice injected with Concanvalin A before partial hepatectomy. This was accompanied with reduced serum interleukin-6 levels. Natural killer T cells play an important role in liver regeneration, which is associated with cyclin B1 and interleukin-6.

  1. Caspases in retinal ganglion cell death and axon regeneration

    Thomas, Chloe N; Berry, Martin; Logan, Ann; Blanch, Richard J; Ahmed, Zubair

    2017-01-01

    Retinal ganglion cells (RGC) are terminally differentiated CNS neurons that possess limited endogenous regenerative capacity after injury and thus RGC death causes permanent visual loss. RGC die by caspase-dependent mechanisms, including apoptosis, during development, after ocular injury and in progressive degenerative diseases of the eye and optic nerve, such as glaucoma, anterior ischemic optic neuropathy, diabetic retinopathy and multiple sclerosis. Inhibition of caspases through genetic or pharmacological approaches can arrest the apoptotic cascade and protect a proportion of RGC. Novel findings have also highlighted a pyroptotic role of inflammatory caspases in RGC death. In this review, we discuss the molecular signalling mechanisms of apoptotic and inflammatory caspase responses in RGC specifically, their involvement in RGC degeneration and explore their potential as therapeutic targets. PMID:29675270

  2. Positional information is reprogrammed in blastema cells of the regenerating limb of the axolotl (Ambystoma mexicanum).

    McCusker, Catherine D; Gardiner, David M

    2013-01-01

    The regenerating region of an amputated salamander limb, known as the blastema, has the amazing capacity to replace exactly the missing structures. By grafting cells from different stages and regions of blastemas induced to form on donor animals expressing Green Fluorescent Protein (GFP), to non-GFP host animals, we have determined that the cells from early stage blastemas, as well as cells at the tip of late stage blastemas are developmentally labile such that their positional identity is reprogrammed by interactions with more proximal cells with stable positional information. In contrast, cells from the adjacent, more proximal stump tissues as well as the basal region of late bud blastemas are positionally stable, and thus form ectopic limb structures when grafted. Finally, we have found that a nerve is required to maintain the blastema cells in a positionally labile state, thus indicating a role for reprogramming cues in the blastema microenvironment.

  3. Positional information is reprogrammed in blastema cells of the regenerating limb of the axolotl (Ambystoma mexicanum.

    Catherine D McCusker

    Full Text Available The regenerating region of an amputated salamander limb, known as the blastema, has the amazing capacity to replace exactly the missing structures. By grafting cells from different stages and regions of blastemas induced to form on donor animals expressing Green Fluorescent Protein (GFP, to non-GFP host animals, we have determined that the cells from early stage blastemas, as well as cells at the tip of late stage blastemas are developmentally labile such that their positional identity is reprogrammed by interactions with more proximal cells with stable positional information. In contrast, cells from the adjacent, more proximal stump tissues as well as the basal region of late bud blastemas are positionally stable, and thus form ectopic limb structures when grafted. Finally, we have found that a nerve is required to maintain the blastema cells in a positionally labile state, thus indicating a role for reprogramming cues in the blastema microenvironment.

  4. European Union - Space of Regeneration, Learning and Innovation in the Context of Sustainable Multidisciplinary Research

    Florin Răzvan Bălășescu

    2010-07-01

    Full Text Available Objective The Lisbon Strategy set a new goal for the EU economy: the transition to a knowledge based economy, competitive and sustainable at macro and regional levels, by creating the European Research Area – a geographic area without frontiers for researches, where scientific resources are better managed to create more jobs and improve Europe's competitiveness. That means an interaction between specific and multidisciplinary research network. Approach However, general research methodology sustains the importance of static and revolutionary specific criteria of Scientific Research Programs but also reveals the natural process of multidisciplinary researches. In this context, the European Union could be regarded as a specific and multidisciplinary research area, as a network of flows, connections, relationships, interdependencies, and interferences between natural - experimental and social-humanistic research spheres (economics, management, sociology and complex systems ecology. Prior Work: In this respect some researchers suggested that both natural and social systems could be considered as multidisciplinary complex adaptive systems consisting of specific cluster network connections ( in the form of biotic and abiotic nodes, respectively, the competitive and regional poles with the ability to continuous self-organizing, learning and regenerating process especially in crisis situations. Implications and Value Paper Utility The present paper might be useful to illustrate the contribution of technical-economic and socio-ecological researches to increasing the sustainability framework of European Research Area by considering the transition from the R&D approach (development through research process to the L&D approach (development through learning process.

  5. GDNF-transduced Schwann cell grafts enhance regeneration of erectile nerves.

    May, Florian; Matiasek, Kaspar; Vroemen, Maurice; Caspers, Christiane; Mrva, Thomas; Arndt, Christian; Schlenker, Boris; Gais, Peter; Brill, Thomas; Buchner, Alexander; Blesch, Armin; Hartung, Rudolf; Stief, Christian; Gansbacher, Bernd; Weidner, Norbert

    2008-11-01

    Schwann cell-seeded guidance tubes have been shown to promote cavernous nerve regeneration, and the local delivery of neurotrophic factors may additionally enhance nerve regenerative capacity. The present study evaluates whether the transplantation of GDNF-overexpressing Schwann cells may enhance regeneration of bilaterally transected erectile nerves in rats. Silicon tubes seeded with either GDNF-overexpressing or GFP-expressing Schwann cells were implanted into the gaps between transected cavernous nerve endings. Six (10 study nerves) or 12 wk (20 study nerves) postoperatively, erectile function was evaluated by relaparotomy, electrical nerve stimulation, and intracavernous pressure recording, followed by ultrastructural evaluation of reconstructed nerves employing bright-field and electron microscopy. Additional animals were either sham-operated (positive control; 20 study nerves) or received bilateral nerve transection without nerve reconstruction (negative control; 20 study nerves). The combination of GDNF delivery and Schwann cell application promoted an intact erectile response in 90% (9 of 10) of grafted nerves after 6 wk and in 95% (19 of 20) after 12 wk, versus 50% (5 of 10) and 80% (16 of 20) of GFP-expressing Schwann cell grafts (p=0.02). The functional recovery was paralleled by enhanced axonal regeneration in GDNF-overexpressing Schwann cell grafts, as indicated by larger cross-sectional areas and a significantly higher percentage of neural tissue compared with GFP-transduced controls. These findings demonstrate that the time required to elicit functional recovery of erectile nerves can be reduced by local delivery of GDNF. In terms of clinical application, this enhanced nerve repair might be critical for timely reinnervation of the corpus cavernosum as a prerequisite for functional recovery in men.

  6. Neural stem cells enhance nerve regeneration after sciatic nerve injury in rats.

    Xu, Lin; Zhou, Shuai; Feng, Guo-Ying; Zhang, Lu-Ping; Zhao, Dong-Mei; Sun, Yi; Liu, Qian; Huang, Fei

    2012-10-01

    With the development of tissue engineering and the shortage of autologous nerve grafts in nerve reconstruction, cell transplantation in a conduit is an alternative strategy to improve nerve regeneration. The present study evaluated the effects and mechanism of brain-derived neural stem cells (NSCs) on sciatic nerve injury in rats. At the transection of the sciatic nerve, a 10-mm gap between the nerve stumps was bridged with a silicon conduit filled with 5 × 10(5) NSCs. In control experiments, the conduit was filled with nerve growth factor (NGF) or normal saline (NS). The functional and morphological properties of regenerated nerves were investigated, and expression of hepatocyte growth factor (HGF) and NGF was measured. One week later, there was no connection through the conduit. Four or eight weeks later, fibrous connections were evident between the proximal and distal segments. Motor function was revealed by measurement of the sciatic functional index (SFI) and sciatic nerve conduction velocity (NCV). Functional recovery in the NSC and NGF groups was significantly more advanced than that in the NS group. NSCs showed significant improvement in axon myelination of the regenerated nerves. Expression of NGF and HGF in the injured sciatic nerve was significantly lower in the NS group than in the NSCs and NGF groups. These results and other advantages of NSCs, such as ease of harvest and relative abundance, suggest that NSCs could be used clinically to enhance peripheral nerve repair.

  7. Retinal ganglion cell survival and axon regeneration after optic nerve injury in naked mole-rats.

    Park, Kevin K; Luo, Xueting; Mooney, Skyler J; Yungher, Benjamin J; Belin, Stephane; Wang, Chen; Holmes, Melissa M; He, Zhigang

    2017-02-01

    In the adult mammalian central nervous system (CNS), axonal damage often triggers neuronal cell death and glial activation, with very limited spontaneous axon regeneration. In this study, we performed optic nerve injury in adult naked mole-rats, the longest living rodent, with a maximum life span exceeding 30 years, and found that injury responses in this species are quite distinct from those in other mammalian species. In contrast to what is seen in other mammals, the majority of injured retinal ganglion cells (RGCs) survive with relatively high spontaneous axon regeneration. Furthermore, injured RGCs display activated signal transducer and activator of transcription-3 (STAT3), whereas astrocytes in the optic nerve robustly occupy and fill the lesion area days after injury. These neuron-intrinsic and -extrinsic injury responses are reminiscent of those in "cold-blooded" animals, such as fish and amphibians, suggesting that the naked mole-rat is a powerful model for exploring the mechanisms of neuronal injury responses and axon regeneration in mammals. J. Comp. Neurol. 525:380-388, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  8. Bone Marrow–Derived Cells Home to and Regenerate Retinal Pigment Epithelium after Injury

    Harris, Jeffrey R.; Brown, Gary A. J.; Jorgensen, Marda; Kaushal, Shalesh; Ellis, E. Ann; Grant, Maria B.; Scott, Edward W.

    2013-01-01

    Purpose To determine whether hematopoietic stem and progenitor cells (HSCs/HPCs) can home to and regenerate the retinal pigment epithelium (RPE) after induced injury. Methods Enriched HSCs/HPCs from green fluorescent protein (gfp) transgenic mice were transplanted into irradiated recipient mice to track bone marrow–derived cells. Physical damage was induced by breaching Bruch’s membrane and inducing vascular endothelial growth factor A (VEGFa) expression to promote neovascularization. RPE damage was also induced by sodium iodate injection (40 mg/kg) into wild-type or albino C57Bl/6 mice. Cell morphology, gfp expression, the presence of the Y chromosome, and the presence of melanosomes were used to determine whether the injured RPE was being repaired by the donor bone marrow. Results Injury to the RPE recruits HSC/HPC–derived cells to incorporate into the RPE layer and differentiate into an RPE phenotype. A portion of the HSCs/HPCs adopt RPE morphology, express melanosomes, and integrate into the RPE without cell fusion. Conclusions HSCs/HPCs can migrate to the RPE layer after physical or chemical injury and regenerate a portion of the damaged cell layer. PMID:16639022

  9. Dye solar cell research

    Cummings, F

    2009-11-01

    Full Text Available Cummings Energy and Processes Materials Science and Manufacturing Council for Scientific and Industrial Research P.O. Box 395 Pretoria 0001, South Africa 27 November 2009 CONTENT head2rightBackground head2rightCSIR Dye Solar Cell Research head2... rightCollaborations and Links © CSIR 2007 www.csir.co.za head2rightAcknowledgements BACKGROUND head2rightSA is dry: Annual rainfall average of 450 mm compared with a world average of 860 mm head2rightOn upside, we have some...

  10. A prosurvival and proangiogenic stem cell delivery system to promote ischemic limb regeneration.

    Xu, Yanyi; Fu, Minghuan; Li, Zhihong; Fan, Zhaobo; Li, Xiaofei; Liu, Ying; Anderson, Peter M; Xie, Xiaoyun; Liu, Zhenguo; Guan, Jianjun

    2016-02-01

    Stem cell therapy is one of the most promising strategies to restore blood perfusion and promote muscle regeneration in ischemic limbs. Yet its therapeutic efficacy remains low owing to the inferior cell survival under the low oxygen and nutrient environment of the injured limbs. To increase therapeutic efficacy, high rates of both short- and long-term cell survival are essential, which current approaches do not support. In this work, we hypothesized that a high rate of short-term cell survival can be achieved by introducing a prosurvival environment into the stem cell delivery system to enhance cell survival before vascularization is established; and that a high rate of long-term cell survival can be attained by building a proangiogenic environment in the system to quickly vascularize the limbs. The system was based on a biodegradable and thermosensitive poly(N-Isopropylacrylamide)-based hydrogel, a prosurvival and proangiogenic growth factor bFGF, and bone marrow-derived mesenchymal stem cells (MSCs). bFGF can be continuously released from the system for 4weeks. The released bFGF significantly improved MSC survival and paracrine effects under low nutrient and oxygen conditions (0% FBS and 1% O2) in vitro. The prosurvival effect of the bFGF on MSCs was resulted from activating cell Kruppel-like factor 4 (KLF4) pathway. When transplanted into the ischemic limbs, the system dramatically improved MSC survival. Some of the engrafted cells were differentiated into skeletal muscle and endothelial cells, respectively. The system also promoted the proliferation of host cells. After only 2weeks of implantation, tissue blood perfusion was completely recovered; and after 4weeks, the muscle fiber diameter was restored similarly to that of the normal limbs. These pronounced results demonstrate that the developed stem cell delivery system has a potential for ischemic limb regeneration. Stem cell therapy is a promising strategy to restore blood perfusion and promote muscle

  11. Immunomodulatory Role of Stem Cell from Human Exfoliated Deciduous Teeth on Periodontal Regeneration.

    Gao, Xianling; Shen, Zongshan; Guan, Meiliang; Huang, Qiting; Chen, Lingling; Qin, Wei; Ge, Xiaohu; Chen, Haijia; Xiao, Yin; Lin, Zhengmei

    2018-03-20

    Periodontitis is initiated by the infection of periodontal bacteria and subsequent tissue inflammation due to immunoreaction, eventually leading to periodontal apparatus loss. Stem cells from human exfoliated deciduous teeth (SHEDs) have exhibited beneficial characteristics in dental tissue regeneration. However, the immunomodulatory functions of SHEDs have not been elucidated in the context of periodontitis treatment. In this study, we investigated the potential immunomodulatory effects of SHEDs on experimental periodontitis and demonstrated that multi-dose delivery of SHEDs led to periodontal tissue regeneration. SHEDs and monocytes/macrophages were cocultured in transwell systems and SHEDs were found to be capable of promoting monocyte/macrophages conversion to CD206+ M2-like phenotype. Bioluminescence imaging (BLI) was employed to assess the survival and distribution of SHEDs after delivery in periodontal tissues in an induced periodontitis model, and BLI revealed that SHEDs survived for approximately 7 days in periodontal tissues with little tissue diffusion. Then, multi-dose SHEDs delivery was applied to treat periodontitis at 7-day intervals. Results showed that muti-dose SHEDs altered the cytokine expression profile in gingival crevicular fluid, reduced gum bleeding, increased new attachment of periodontal ligament and decreased osteoclast differentiation. Micro-computed tomography analysis showed SHEDs administration significantly increased periodontal regeneration and alveolar bone volume, and decreased distance of cementoenamel junction to alveolar bone crest (CEJ-ABC). Furthermore, an increase in the number of CD206+ M2 macrophages was observed in periodontal tissues following the delivery of SHEDs, which aligned well with the promoted conversion to CD206+ M2-like cells from monocytes/macrophages in vitro after stimulation by SHEDs. This study demonstrated in a rat periodontitis model that local delivery of SHEDs attributed to the induction of M2

  12. Capillary regeneration in scleroderma: stem cell therapy reverses phenotype?

    Jo N Fleming

    2008-01-01

    Full Text Available Scleroderma is an autoimmune disease with a characteristic vascular pathology. The vasculopathy associated with scleroderma is one of the major contributors to the clinical manifestations of the disease.We used immunohistochemical and mRNA in situ hybridization techniques to characterize this vasculopathy and showed with morphometry that scleroderma has true capillary rarefaction. We compared skin biopsies from 23 scleroderma patients and 24 normal controls and 7 scleroderma patients who had undergone high dose immunosuppressive therapy followed by autologous hematopoietic cell transplant. Along with the loss of capillaries there was a dramatic change in endothelial phenotype in the residual vessels. The molecules defining this phenotype are: vascular endothelial cadherin, a supposedly universal endothelial marker required for tube formation (lost in the scleroderma tissue, antiangiogenic interferon alpha (overexpressed in the scleroderma dermis and RGS5, a signaling molecule whose expression coincides with the end of branching morphogenesis during development and tumor angiogenesis (also overexpressed in scleroderma skin. Following high dose immunosuppressive therapy, patients experienced clinical improvement and 5 of the 7 patients with scleroderma had increased capillary counts. It was also observed in the same 5 patients, that the interferon alpha and vascular endothelial cadherin had returned to normal as other clinical signs in the skin regressed, and in all 7 patients, RGS5 had returned to normal.These data provide the first objective evidence for loss of vessels in scleroderma and show that this phenomenon is reversible. Coordinate changes in expression of three molecules already implicated in angiogenesis or anti-angiogenesis suggest that control of expression of these three molecules may be the underlying mechanism for at least the vascular component of this disease. Since rarefaction has been little studied, these data may have

  13. The yield of genome mutations in cells of intact and regenerating rat liver in normal conditions and after γ-irradiation

    Gil'yano, N.Ya.; Malinovskij, O.V.

    1984-01-01

    A comparative study was made of spontaneus and induced polyploidy in cells of resting and regenerating rat liver. Polyploidy was shown to play a major role in the ontogenesis and during regeneration after partial hepatectomy. An essential difference was revealed in the radiation response of cells of intact and regenerating liver with respect to the yield of polyploid cells. This distinction was referped to different effectiveness of the processes of repair and fixation of radiation damages in the actively proliferating and resting cells

  14. Live fate-mapping of joint-associated fibroblasts visualizes expansion of cell contributions during zebrafish fin regeneration.

    Tornini, Valerie A; Thompson, John D; Allen, Raymond L; Poss, Kenneth D

    2017-08-15

    The blastema is a mass of progenitor cells responsible for regeneration of amputated salamander limbs and fish fins. Previous studies have indicated that resident cell sources producing the blastema contribute lineage-restricted progeny to regenerating tissue. However, these studies have labeled general cell types rather than granular cell subpopulations, and they do not explain the developmental transitions that must occur for distal structures to arise from cells with proximal identities in the appendage stump. Here, we find that regulatory sequences of tph1b , which encodes an enzyme that synthesizes serotonin, mark a subpopulation of fibroblast-like cells restricted to the joints of uninjured adult zebrafish fins. Amputation stimulates serotonin production in regenerating fin fibroblasts, yet targeted tph1b mutations abrogating this response do not disrupt fin regeneration. In uninjured animals, tph1b -expressing cells contribute fibroblast progeny that remain restricted to joints throughout life. By contrast, upon amputation, tph1b + joint cells give rise to fibroblasts that distribute across the entire lengths of regenerating fin rays. Our experiments visualize and quantify how incorporation into an appendage blastema broadens the progeny contributions of a cellular subpopulation that normally has proximodistal restrictions. © 2017. Published by The Company of Biologists Ltd.

  15. Uterine-derived progenitor cells are immunoprivileged and effectively improve cardiac regeneration when used for cell therapy.

    Ludke, Ana; Wu, Jun; Nazari, Mansoreh; Hatta, Kota; Shao, Zhengbo; Li, Shu-Hong; Song, Huifang; Ni, Nathan C; Weisel, Richard D; Li, Ren-Ke

    2015-07-01

    Cell therapy to prevent cardiac dysfunction after myocardial infarction (MI) is less effective in aged patients because aged cells have decreased regenerative capacity. Allogeneic transplanted stem cells (SCs) from young donors are usually rejected. Maintaining transplanted SC immunoprivilege may dramatically improve regenerative outcomes. The uterus has distinct immune characteristics, and we showed that reparative uterine SCs home to the myocardium post-MI. Here, we identify immunoprivileged uterine SCs and assess their effects on cardiac regeneration after allogeneic transplantation. We found more than 20% of cells in the mouse uterus have undetectable MHC I expression by flow cytometry. Uterine MHC I((neg)) and MHC I((pos)) cells were separated by magnetic cell sorting. The MHC I((neg)) population expressed the SC markers CD34, Sca-1 and CD90, but did not express MHC II or c-kit. In vitro, MHC I((neg)) and ((pos)) SCs show colony formation and endothelial differentiation capacity. In mixed leukocyte co-culture, MHC I((neg)) cells showed reduced cell death and leukocyte proliferation compared to MHC I((pos)) cells. MHC I((neg)) and ((pos)) cells had significantly greater angiogenic capacity than mesenchymal stem cells. The benefits of intramyocardial injection of allogeneic MHC I((neg)) cells after MI were comparable to syngeneic bone marrow cell transplantation, with engraftment in cardiac tissue and limited recruitment of CD4 and CD8 cells up to 21 days post-MI. MHC I((neg)) cells preserved cardiac function, decreased infarct size and improved regeneration post-MI. This new source of immunoprivileged cells can induce neovascularization and could be used as allogeneic cell therapy for regenerative medicine. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. THE FUNCTIONAL EFFECTIVENESS OF A CELL-ENGINEERED CONSTRUCT FOR THE REGENERATION OF ARTICULAR CARTILAGE

    V. I. Sevastianov

    2015-01-01

    Full Text Available The aim of this study is an analysis of the functional effectiveness of a biomedical cell product consisting of a biopolymer microheterogeneous collagen-containing hydrogel (BMCH, human adipose-derived mesenchymal stromal cells (hADMSCs, and chondrogenic induction medium in the regeneration of articular cartilage. Materials and methods. The test model of the adjuvant arthritis was used (female Soviet Chinchilla rabbits with the further development into osteoarthrosis (OA combined with the clinical, biochemical, radiological, and histochemical trials. Results. On Day 92 of the OA model it has been found that the intra-articular introduction of a BMCH with hADMSCs into the left knee joint (n = 3 30 days after the OA modeling, as opposed to the right joint (negative control, n = 3, stimulates the regenerative processes of the cartilaginous tissue structure characterized by the formation of chondrocyte «columns», the emergence of isogenic groups in the intracellular matrix and the regeneration of its structure. Upon the intra-articular introduction of a BMCH (n = 3 such effects are markedly less pronounced. Conclusions. A significant regenerative potential of a cell-engineered construct of human articular tissue (CEC ATh has been proven. It is possible to presume that biostimulating properties of CEC ATh are due to the activating effect of a biomedical cell product on the stem cell migration processes from the surrounding tissue into the injured area with their subsequent differentiation. 

  17. Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase.

    Fischer, Kimberlee M; Cottage, Christopher T; Wu, Weitao; Din, Shabana; Gude, Natalie A; Avitabile, Daniele; Quijada, Pearl; Collins, Brett L; Fransioli, Jenna; Sussman, Mark A

    2009-11-24

    Despite numerous studies demonstrating the efficacy of cellular adoptive transfer for therapeutic myocardial regeneration, problems remain for donated cells with regard to survival, persistence, engraftment, and long-term benefits. This study redresses these concerns by enhancing the regenerative potential of adoptively transferred cardiac progenitor cells (CPCs) via genetic engineering to overexpress Pim-1, a cardioprotective kinase that enhances cell survival and proliferation. Intramyocardial injections of CPCs overexpressing Pim-1 were given to infarcted female mice. Animals were monitored over 4, 12, and 32 weeks to assess cardiac function and engraftment of Pim-1 CPCs with echocardiography, in vivo hemodynamics, and confocal imagery. CPCs overexpressing Pim-1 showed increased proliferation and expression of markers consistent with cardiogenic lineage commitment after dexamethasone exposure in vitro. Animals that received CPCs overexpressing Pim-1 also produced greater levels of cellular engraftment, persistence, and functional improvement relative to control CPCs up to 32 weeks after delivery. Salutary effects include reduction of infarct size, greater number of c-kit(+) cells, and increased vasculature in the damaged region. Myocardial repair is significantly enhanced by genetic engineering of CPCs with Pim-1 kinase. Ex vivo gene delivery to enhance cellular survival, proliferation, and regeneration may overcome current limitations of stem cell-based therapeutic approaches.

  18. Expression of basal cell marker revealed by RAM11 antibody during epithelial regeneration in rabbits.

    Tadeusz Cichocki

    2010-06-01

    Full Text Available RAM11 is a mouse monoclonal anti-rabbit macrophage antibody recognizing connective tissue and vascular macrophages. Our previous report showed that RAM11 reacted with basal cells of stratified squamous epithelia of rabbit skin, oral mucosa and esophagus. The aim of the present study was to follow the appearance of RAM11 immunoreactivity in basal cells of regenerating oral epithelium in rabbits. No RAM11 immunostaining was observed in the regenerating epithelium examined on days 1 and 3 of wound healing. A weak immunofluorescence first appeared on day 7 in single basal cells and 32% of RAM11- positive basal cells were observed on day 14. These findings indicate that expression of the antigen recognized by RAM11 antibody is a transient event in the differentiation of oral keratinocytes which not always occurs during epithelial repair, although it is a constant feature of epithelial turnover in mature epithelium. Therefore this antigen can be regarded as basal cell marker only in mature stratified squamous epithelia.

  19. Mesenchymal Stem Cells Enhance Liver Regeneration via Improving Lipid Accumulation and Hippo Signaling

    Yang Liu

    2018-01-01

    Full Text Available The liver has the potential to regenerate after injury. It is a challenge to improve liver regeneration (LR after liver resection in clinical practice. Bone morrow-derived mesenchymal stem cells (MSCs have shown to have a role in various liver diseases. To explore the effects of MSCs on LR, we established a model of 70% partial hepatectomy (PHx. Results revealed that infusion of MSCs could improve LR through enhancing cell proliferation and cell growth during the first 2 days after PHx, and MSCs could also restore liver synthesis function. Infusion of MSCs also improved liver lipid accumulation partly via mechanistic target of rapamycin (mTOR signaling and enhanced lipid β-oxidation support energy for LR. Rapamycin-induced inhibition of mTOR decreased liver lipid accumulation at 24 h after PHx, leading to impaired LR. And after infusion of MSCs, a proinflammatory environment formed in the liver, evidenced by increased expression of IL-6 and IL-1β, and thus the STAT3 and Hippo-YAP pathways were activated to improve cell proliferation. Our results demonstrated the function of MSCs on LR after PHx and provided new evidence for stem cell therapy of liver diseases.

  20. Stimulation of angiogenesis, neurogenesis and regeneration by side population cells from dental pulp.

    Ishizaka, Ryo; Hayashi, Yuki; Iohara, Koichiro; Sugiyama, Masahiko; Murakami, Masashi; Yamamoto, Tsubasa; Fukuta, Osamu; Nakashima, Misako

    2013-03-01

    Mesenchymal stem cells (MSCs) have been used for cell therapy in various experimental disease models. However, the regenerative potential of MSCs from different tissue sources and the influence of the tissue niche have not been investigated. In this study, we compared the regenerative potential of dental pulp, bone marrow and adipose tissue-derived CD31(-) side population (SP) cells isolated from an individual porcine source. Pulp CD31(-) SP cells expressed the highest levels of angiogenic/neurotrophic factors and had the highest migration activity. Conditioned medium from pulp CD31(-) SP cells produced potent anti-apoptotic activity and neurite outgrowth, compared to those from bone marrow and adipose CD31(-) SP cells. Transplantation of pulp CD31(-) SP cells in a mouse hindlimb ischemia model produced higher blood flow and capillary density than transplantation of bone marrow and adipose CD31(-) SP cells. Motor function recovery and infarct size reduction were greater with pulp CD31(-) SP cells. Pulp CD31(-) SP cells induced maximal angiogenesis, neurogenesis and pulp regeneration in ectopic transplantation models compared to other tissue sources. These results demonstrate that pulp stem cells have higher angiogenic, neurogenic and regenerative potential and may therefore be superior to bone marrow and adipose stem cells for cell therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Engineering bone regeneration with novel cell-laden hydrogel microfiber-injectable calcium phosphate scaffold

    Song, Yang [Department of Prosthodontics, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong (China); Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD 21201 (United States); Zhang, Chi [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041 (China); Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD 21201 (United States); Wang, Ping, E-mail: dentistping@gmail.com [Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD 21201 (United States); Wang, Lin [Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD 21201 (United States); VIP Integrated Department, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130011 (China); Bao, Chunyun [State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041 (China); Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD 21201 (United States); Weir, Michael D.; Reynolds, Mark A. [Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD 21201 (United States); Ren, Ke [Department of Neural and Pain Sciences, School of Dentistry, Program in Neuroscience, University of Maryland, Baltimore, MD 21201 (United States); Zhao, Liang, E-mail: lzhaonf@126.com [Department of Endodontics, Periodontics and Prosthodontics, University of Maryland School of Dentistry, Baltimore, MD 21201 (United States); Department of Orthopaedic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515 (China); and others

    2017-06-01

    Cell-based tissue engineering is promising to create living functional tissues for bone regeneration. The implanted cells should be evenly distributed in the scaffold, be fast-released to the defect and maintain high viability in order to actively participate in the regenerative process. Herein, we report an injectable calcium phosphate cement (CPC) scaffold containing cell-encapsulating hydrogel microfibers with desirable degradability that could deliver cells in a timely manner and maintain cell viability. Microfibers were synthesized using partially-oxidized alginate with various concentrations (0–0.8%) of fibrinogen to optimize the degradation rate of the alginate-fibrin microfibers (Alg-Fb MF). A fibrin concentration of 0.4% in Alg-Fb MF resulted in the greatest enhancement of cell migration, release and proliferation. Interestingly, a significant amount of cell–cell contact along the long-axis of the microfibers was established in Alg-0.4%Fb MF as early as day 2. The injectable tissue engineered construct for bone reconstruct was fabricated by mixing the fast-degradable Alg-0.4%Fb MF with CPC paste at 1:1 volume ratio. In vitro study showed that cells re-collected from the construct maintained good viability and osteogenic potentials. In vivo study demonstrated that the hBMSC-encapsulated CPC-MF tissue engineered construct displayed a robust capacity for bone regeneration. At 12 weeks after implantation, osseous bridge in the rat mandibular defect was observed in CPC-MF-hBMSCs group with a new bone area fraction of (42.1 ± 7.8) % in the defects, which was > 3-fold that of the control group. The novel tissue-engineered construct presents an excellent prospect for a wide range of dental, craniofacial and orthopedic applications. - Highlights: • Microfibers protected cells during CPC mixing and injection, and supported the viability, migration and differentiation of encapsulated cells. • Cells re-collected from the construct maintained good viability

  2. Engineering bone regeneration with novel cell-laden hydrogel microfiber-injectable calcium phosphate scaffold

    Song, Yang; Zhang, Chi; Wang, Ping; Wang, Lin; Bao, Chunyun; Weir, Michael D.; Reynolds, Mark A.; Ren, Ke; Zhao, Liang

    2017-01-01

    Cell-based tissue engineering is promising to create living functional tissues for bone regeneration. The implanted cells should be evenly distributed in the scaffold, be fast-released to the defect and maintain high viability in order to actively participate in the regenerative process. Herein, we report an injectable calcium phosphate cement (CPC) scaffold containing cell-encapsulating hydrogel microfibers with desirable degradability that could deliver cells in a timely manner and maintain cell viability. Microfibers were synthesized using partially-oxidized alginate with various concentrations (0–0.8%) of fibrinogen to optimize the degradation rate of the alginate-fibrin microfibers (Alg-Fb MF). A fibrin concentration of 0.4% in Alg-Fb MF resulted in the greatest enhancement of cell migration, release and proliferation. Interestingly, a significant amount of cell–cell contact along the long-axis of the microfibers was established in Alg-0.4%Fb MF as early as day 2. The injectable tissue engineered construct for bone reconstruct was fabricated by mixing the fast-degradable Alg-0.4%Fb MF with CPC paste at 1:1 volume ratio. In vitro study showed that cells re-collected from the construct maintained good viability and osteogenic potentials. In vivo study demonstrated that the hBMSC-encapsulated CPC-MF tissue engineered construct displayed a robust capacity for bone regeneration. At 12 weeks after implantation, osseous bridge in the rat mandibular defect was observed in CPC-MF-hBMSCs group with a new bone area fraction of (42.1 ± 7.8) % in the defects, which was > 3-fold that of the control group. The novel tissue-engineered construct presents an excellent prospect for a wide range of dental, craniofacial and orthopedic applications. - Highlights: • Microfibers protected cells during CPC mixing and injection, and supported the viability, migration and differentiation of encapsulated cells. • Cells re-collected from the construct maintained good viability

  3. Fuel Cell Research

    Weber, Peter M. [Brown University

    2014-03-30

    Executive Summary In conjunction with the Brown Energy Initiative, research Projects selected for the fuel cell research grant were selected on the following criteria: They should be fundamental research that has the potential to significantly impact the nation’s energy infrastructure. They should be scientifically exciting and sound. They should synthesize new materials, lead to greater insights, explore new phenomena, or design new devices or processes that are of relevance to solving the energy problems. They involve top-caliper senior scientists with a record of accomplishment, or junior faculty with outstanding promise of achievement. They should promise to yield at least preliminary results within the given funding period, which would warrant further research development. They should fit into the overall mission of the Brown Energy Initiative, and the investigators should contribute as partners to an intellectually stimulating environment focused on energy science. Based on these criteria, fourteen faculty across three disciplines (Chemistry, Physics and Engineering) and the Charles Stark Draper Laboratory were selected to participate in this effort.1 In total, there were 30 people supported, at some level, on these projects. This report highlights the findings and research outcomes of the participating researchers.

  4. STAT3 Controls the Long-Term Survival and Phenotype of Repair Schwann Cells during Nerve Regeneration.

    Benito, Cristina; Davis, Catherine M; Gomez-Sanchez, Jose A; Turmaine, Mark; Meijer, Dies; Poli, Valeria; Mirsky, Rhona; Jessen, Kristjan R

    2017-04-19

    After nerve injury, Schwann cells convert to a phenotype specialized to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signaling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role. It supports the long-term survival of repair Schwann cells and is required for the maintenance of repair Schwann cell properties. In contrast, STAT3 is less important for the initial generation of repair Schwann cells after injury. In repair Schwann cells, we find that Schwann cell STAT3 activation by Tyr705 phosphorylation is sustained during long-term denervation. STAT3 is required for maintaining autocrine Schwann cell survival signaling, and inactivation of Schwann cell STAT3 results in a striking loss of repair cells from chronically denervated distal stumps. STAT3 inactivation also results in abnormal morphology of repair cells and regeneration tracks, and failure to sustain expression of repair cell markers, including Shh, GDNF, and BDNF. Because Schwann cell development proceeds normally without STAT3, the function of this factor appears restricted to Schwann cells after injury. This identification of transcriptional mechanisms that support long-term survival and differentiation of repair cells will help identify, and eventually correct, the failures that lead to the deterioration of this important cell population. SIGNIFICANCE STATEMENT Although injured peripheral nerves contain repair Schwann cells that provide signals and spatial clues for promoting regeneration, the clinical outcome after nerve damage is frequently poor. A key reason for this is that, during the slow growth of axons through the proximal

  5. Human Breast Cancer Cells Are Redirected to Mammary Epithelial Cells upon Interaction with the Regenerating Mammary Gland Microenvironment In-Vivo

    Bussard, Karen M.; Smith, Gilbert H.

    2012-01-01

    Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display ‘normal’ behavior when placed into ‘normal’ ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for ‘normal’ gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts) confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini) were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic) respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo. PMID:23155468

  6. Human breast cancer cells are redirected to mammary epithelial cells upon interaction with the regenerating mammary gland microenvironment in-vivo.

    Karen M Bussard

    Full Text Available Breast cancer is the second leading cause of cancer deaths in the United States. At present, the etiology of breast cancer is unknown; however the possibility of a distinct cell of origin, i.e. a cancer stem cell, is a heavily investigated area of research. Influencing signals from the tissue niche are known to affect stem cells. Literature has shown that cancer cells lose their tumorigenic potential and display 'normal' behavior when placed into 'normal' ontogenic environments. Therefore, it may be the case that the tissue microenvironment is able to generate signals to redirect cancer cell fate. Previously, we showed that pluripotent human embryonal carcinoma cells could be redirected by the regenerating mammary gland microenvironment to contribute epithelial progeny for 'normal' gland development in-vivo. Here, we show that that human metastatic, non-metastatic, and metastasis-suppressed breast cancer cells proliferate and contribute to normal mammary gland development in-vivo without tumor formation. Immunochemistry for human-specific mitochondria, keratin 8 and 14, as well as human-specific milk proteins (alpha-lactalbumin, impregnated transplant hosts confirmed the presence of human cell progeny. Features consistent with normal mammary gland development as seen in intact hosts (duct, lumen formation, development of secretory acini were recapitulated in both primary and secondary outgrowths from chimeric implants. These results suggest the dominance of the tissue microenvironment over cancer cell fate. This work demonstrates that cultured human breast cancer cells (metastatic and non-metastatic respond developmentally to signals generated by the mouse mammary gland microenvironment during gland regeneration in-vivo.

  7. Adult Lung Spheroid Cells Contain Progenitor Cells and Mediate Regeneration in Rodents With Bleomycin-Induced Pulmonary Fibrosis.

    Henry, Eric; Cores, Jhon; Hensley, M Taylor; Anthony, Shirena; Vandergriff, Adam; de Andrade, James B M; Allen, Tyler; Caranasos, Thomas G; Lobo, Leonard J; Cheng, Ke

    2015-11-01

    Lung diseases are devastating conditions and ranked as one of the top five causes of mortality worldwide according to the World Health Organization. Stem cell therapy is a promising strategy for lung regeneration. Previous animal and clinical studies have focused on the use of mesenchymal stem cells (from other parts of the body) for lung regenerative therapies. We report a rapid and robust method to generate therapeutic resident lung progenitors from adult lung tissues. Outgrowth cells from healthy lung tissue explants are self-aggregated into three-dimensional lung spheroids in a suspension culture. Without antigenic sorting, the lung spheroids recapitulate the stem cell niche and contain a natural mixture of lung stem cells and supporting cells. In vitro, lung spheroid cells can be expanded to a large quantity and can form alveoli-like structures and acquire mature lung epithelial phenotypes. In severe combined immunodeficiency mice with bleomycin-induced pulmonary fibrosis, intravenous injection of human lung spheroid cells inhibited apoptosis, fibrosis, and infiltration but promoted angiogenesis. In a syngeneic rat model of pulmonary fibrosis, lung spheroid cells outperformed adipose-derived mesenchymal stem cells in reducing fibrotic thickening and infiltration. Previously, lung spheroid cells (the spheroid model) had only been used to study lung cancer cells. Our data suggest that lung spheroids and lung spheroid cells from healthy lung tissues are excellent sources of regenerative lung cells for therapeutic lung regeneration. The results from the present study will lead to future human clinical trials using lung stem cell therapies to treat various incurable lung diseases, including pulmonary fibrosis. The data presented here also provide fundamental knowledge regarding how injected stem cells mediate lung repair in pulmonary fibrosis. ©AlphaMed Press.

  8. Distal Regeneration Involves the Age Dependent Activity of Branchial Sac Stem Cells in the Ascidian Ciona intestinalis.

    Jeffery, William R

    2015-02-01

    Tunicates have high capacities for regeneration but the underlying mechanisms and their relationship to life cycle progression are not well understood. Here we investigate the regeneration of distal structures in the ascidian tunicate Ciona intestinalis . Analysis of regenerative potential along the proximal-distal body axis indicated that distal organs, such as the siphons, their pigmented sensory organs, and the neural complex, could only be replaced from body fragments containing the branchial sac. Distal regeneration involves the formation of a blastema composed of cells that undergo cell proliferation prior to differentiation and cells that differentiate without cell proliferation. Both cell types originate in the branchial sac and appear in the blastema at different times after distal injury. Whereas the branchial sac stem cells are present in young animals, they are depleted in old animals that have lost their regeneration capacity. Thus Ciona adults contain a population of age-related stem cells located in the branchial sac that are a source of precursors for distal body regeneration.

  9. Distal regeneration involves the age dependent activity of branchial sac stem cells in the ascidian Ciona intestinalis

    2014-01-01

    Abstract Tunicates have high capacities for regeneration but the underlying mechanisms and their relationship to life cycle progression are not well understood. Here we investigate the regeneration of distal structures in the ascidian tunicate Ciona intestinalis. Analysis of regenerative potential along the proximal−distal body axis indicated that distal organs, such as the siphons, their pigmented sensory organs, and the neural complex, could only be replaced from body fragments containing the branchial sac. Distal regeneration involves the formation of a blastema composed of cells that undergo cell proliferation prior to differentiation and cells that differentiate without cell proliferation. Both cell types originate in the branchial sac and appear in the blastema at different times after distal injury. Whereas the branchial sac stem cells are present in young animals, they are depleted in old animals that have lost their regeneration capacity. Thus Ciona adults contain a population of age‐related stem cells located in the branchial sac that are a source of precursors for distal body regeneration. PMID:25893097

  10. Pulp regeneration by transplantation of dental pulp stem cells in pulpitis: a pilot clinical study.

    Nakashima, Misako; Iohara, Koichiro; Murakami, Masashi; Nakamura, Hiroshi; Sato, Yayoi; Ariji, Yoshiko; Matsushita, Kenji

    2017-03-09

    Experiments have previously demonstrated the therapeutic potential of mobilized dental pulp stem cells (MDPSCs) for complete pulp regeneration. The aim of the present pilot clinical study is to assess the safety, potential efficacy, and feasibility of autologous transplantation of MDPSCs in pulpectomized teeth. Five patients with irreversible pulpitis were enrolled and monitored for up to 24 weeks following MDPSC transplantation. The MDPSCs were isolated from discarded teeth and expanded based on good manufacturing practice (GMP). The quality of the MDPSCs at passages 9 or 10 was ascertained by karyotype analyses. The MDPSCs were transplanted with granulocyte colony-stimulating factor (G-CSF) in atelocollagen into pulpectomized teeth. The clinical and laboratory evaluations demonstrated no adverse events or toxicity. The electric pulp test (EPT) of the pulp at 4 weeks demonstrated a robust positive response. The signal intensity of magnetic resonance imaging (MRI) of the regenerated tissue in the root canal after 24 weeks was similar to that of normal dental pulp in the untreated control. Finally, cone beam computed tomography demonstrated functional dentin formation in three of the five patients. Human MDPSCs are safe and efficacious for complete pulp regeneration in humans in this pilot clinical study.

  11. Organ-level quorum sensing directs regeneration in hair stem cell populations

    Chen, Chih-Chiang; Wang, Lei; Plikus, Maksim V.; Jiang, Ting Xin; Murray, Philip J.; Ramos, Raul; Guerrero-Juarez, Christian F.; Hughes, Michael W; Lee, Oscar K.; Shi, Songtao; Widelitz, Randall B.; Lander, Arthur D.; Chuong, Cheng Ming

    2015-01-01

    SUMMARY Coordinated organ behavior is crucial for an effective response to environmental stimuli. By studying regeneration of hair follicles in response to patterned hair removal, we demonstrate that organ-level quorum sensing allows coordinated responses to skin injury. Removing hair at different densities leads to a regeneration of up to 5 times more neighboring, unplucked resting hairs, indicating activation of a collective decision-making process. Through data modeling, the range of the quorum signal was estimated to be on the order of 1 mm, greater than expected for a diffusible molecular cue. Molecular and genetic analysis uncovered a two-step mechanism, where release of CCL2 from injured hairs leads to recruitment of TNF-α secreting macrophages, which accumulate and signal to both plucked and unplucked follicles. By coupling immune response with regeneration, this mechanism allows skin to respond predictively to distress, disregarding mild injury, while meeting stronger injury with full-scale cooperative activation of stem cells. PMID:25860610

  12. A polymer foam conduit seeded with Schwann cells promotes guided peripheral nerve regeneration.

    Hadlock, T; Sundback, C; Hunter, D; Cheney, M; Vacanti, J P

    2000-04-01

    Alternatives to autografts have long been sought for use in bridging neural gaps. Many entubulation materials have been studied, although with generally disappointing results in comparison with autografts. The purpose of this study was to design a more effective neural guidance conduit, to introduce Schwann cells into the conduit, and to determine regenerative capability through it in an in vivo model. A novel, fully biodegradable polymer conduit was designed and fabricated for use in peripheral nerve repair, which approximates the macro- and microarchitecture of native peripheral nerves. It comprised a series of longitudinally aligned channels, with diameters ranging from 60 to 550 microns. The lumenal surfaces promoted the adherence of Schwann cells, whose presence is known to play a key role in nerve regeneration. This unique channel architecture increased the surface area available for Schwann cell adherence up to five-fold over that available through a simple hollow conduit. The conduit was composed of a high-molecular-weight copolymer of lactic and glycolic acids (PLGA) (MW 130,000) in an 85:15 monomer ratio. A novel foam-processing technique, employing low-pressure injection molding, was used to create highly porous conduits (approximately 90% pore volume) with continuous longitudinal channels. Using this technique, conduits were constructed containing 1, 5, 16, 45, or more longitudinally aligned channels. Prior to cellular seeding of these conduits, the foams were prewet with 50% ethanol, flushed with physiologic saline, and coated with laminin solution (10 microg/mL). A Schwann cell suspension was dynamically introduced into these processed foams at a concentration of 5 X 10(5) cells/mL, using a simple bioreactor flow loop. In vivo regeneration studies were carried out in which cell-laden five-channel polymer conduits (individual channel ID 500 microm, total conduit OD 2.3 mm) were implanted across a 7-mm gap in the rat sciatic nerve (n = 4), and midgraft

  13. Solid freeform-fabricated scaffolds designed to carry multicellular mesenchymal stem cell spheroids for cartilage regeneration

    G-S Huang

    2013-10-01

    Full Text Available Three-dimensional (3D cellular spheroids have recently emerged as a new trend to replace suspended single cells in modern cell-based therapies because of their greater regeneration capacities in vitro. They may lose the 3D structure during a change of microenvironment, which poses challenges to their translation in vivo. Besides, the conventional microporous scaffolds may have difficulty in accommodating these relatively large spheroids. Here we revealed a novel design of microenvironment for delivering and sustaining the 3D spheroids. Biodegradable scaffolds with macroporosity to accommodate mesenchymal stem cell (MSC spheroids were made by solid freeform fabrication (SFF from the solution of poly(D,L-lactide-co-glycolide. Their internal surface was modified with chitosan following air plasma treatment in order to preserve the morphology of the spheroids. It was demonstrated that human MSC spheroids loaded in SFF scaffolds produced a significantly larger amount of cartilage-associated extracellular matrix in vitro and in NOD/SCID mice compared to single cells in the same scaffolds. Implantation of MSC spheroid-loaded scaffolds into the chondral defects of rabbit knees showed superior cartilage regeneration. This study establishes new perspectives in designing the spheroid-sustaining microenvironment within a tissue engineering scaffold for in vivo applications.

  14. Xiphoid Process-Derived Chondrocytes: A Novel Cell Source for Elastic Cartilage Regeneration

    Nam, Seungwoo; Cho, Wheemoon; Cho, Hyunji; Lee, Jungsun

    2014-01-01

    Reconstruction of elastic cartilage requires a source of chondrocytes that display a reliable differentiation tendency. Predetermined tissue progenitor cells are ideal candidates for meeting this need; however, it is difficult to obtain donor elastic cartilage tissue because most elastic cartilage serves important functions or forms external structures, making these tissues indispensable. We found vestigial cartilage tissue in xiphoid processes and characterized it as hyaline cartilage in the proximal region and elastic cartilage in the distal region. Xiphoid process-derived chondrocytes (XCs) showed superb in vitro expansion ability based on colony-forming unit fibroblast assays, cell yield, and cumulative cell growth. On induction of differentiation into mesenchymal lineages, XCs showed a strong tendency toward chondrogenic differentiation. An examination of the tissue-specific regeneration capacity of XCs in a subcutaneous-transplantation model and autologous chondrocyte implantation model confirmed reliable regeneration of elastic cartilage regardless of the implantation environment. On the basis of these observations, we conclude that xiphoid process cartilage, the only elastic cartilage tissue source that can be obtained without destroying external shape or function, is a source of elastic chondrocytes that show superb in vitro expansion and reliable differentiation capacity. These findings indicate that XCs could be a valuable cell source for reconstruction of elastic cartilage. PMID:25205841

  15. Acceleration of Regeneration of Large Gap Peripheral Nerve Injuries Using Acellular Nerve Allografts plus amniotic Fluid Derived Stem Cells (AFS)

    2016-09-01

    AWARD NUMBER: W811XWH-13-1-0310 TITLE: Acceleration of Regeneration of Large-Gap Peripheral Nerve Injuries Using Acellular Nerve Allografts...plus amniotic Fluid Derived Stem Cells (AFS). PRINCIPAL INVESTIGATOR: Zhongyu Li, MD, PhD RECIPIENT: Wake Forest University Health Sciences...REPORT DATE September 2016 2. REPORT TYPE Annual 3. DATES COVERED 1Sep2015 - 31Aug2016 4. TITLE AND SUBTITLE Acceleration of Regeneration of Large

  16. Information on Stem Cell Research

    ... Home » Current Research » Focus on Research Focus on Stem Cell Research Stem cells possess the unique ability to differentiate into ... virus infection. To search the complete list of stem cell research projects funded by NIH please go to NIH ...

  17. Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration.

    Aquino-Martínez, Rubén; Angelo, Alcira P; Pujol, Francesc Ventura

    2017-11-16

    Osteoinduction and subsequent bone formation rely on efficient mesenchymal stem cell (MSC) recruitment. It is also known that migration is induced by gradients of growth factors and cytokines. Degradation of Ca 2+ -containing biomaterials mimics the bone remodeling compartment producing a localized calcium-rich osteoinductive microenvironment. The aim of our study was to determine the effect of calcium sulfate (CaSO 4 ) on MSC migration. In addition, to evaluate the influence of CaSO 4 on MSC differentiation and the potential molecular mechanisms involved. A circular calvarial bone defect (5 mm diameter) was created in the parietal bone of 35 Balb-C mice. We prepared and implanted a cell-free agarose/gelatin scaffold alone or in combination with different CaSO 4 concentrations into the bone defects. After 7 weeks, we determined the new bone regenerated by micro-CT and histological analysis. In vitro, we evaluated the CaSO 4 effects on MSC migration by both wound healing and agarose spot assays. Osteoblastic gene expression after BMP-2 and CaSO 4 treatment was also evaluated by qPCR. CaSO 4 increased MSC migration and bone formation in a concentration-dependent manner. Micro-CT analysis showed that the addition of CaSO 4 significantly enhanced bone regeneration compared to the scaffold alone. The histological evaluation confirmed an increased number of endogenous cells recruited into the cell-free CaSO 4 -containing scaffolds. Furthermore, MSC migration in vitro and active AKT levels were attenuated when CaSO 4 and BMP-2 were in combination. Addition of LY294002 and Wortmannin abrogated the CaSO 4 effects on MSC migration. Specific CaSO 4 concentrations induce bone regeneration of calvarial defects in part by acting on the host's undifferentiated MSCs and promoting their migration. Progenitor cell recruitment is followed by a gradual increment in osteoblast gene expression. Moreover, CaSO 4 regulates BMP-2-induced MSC migration by differentially activating the PI3

  18. Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration

    Rubén Aquino-Martínez

    2017-11-01

    Full Text Available Abstract Background Osteoinduction and subsequent bone formation rely on efficient mesenchymal stem cell (MSC recruitment. It is also known that migration is induced by gradients of growth factors and cytokines. Degradation of Ca2+-containing biomaterials mimics the bone remodeling compartment producing a localized calcium-rich osteoinductive microenvironment. The aim of our study was to determine the effect of calcium sulfate (CaSO4 on MSC migration. In addition, to evaluate the influence of CaSO4 on MSC differentiation and the potential molecular mechanisms involved. Methods A circular calvarial bone defect (5 mm diameter was created in the parietal bone of 35 Balb-C mice. We prepared and implanted a cell-free agarose/gelatin scaffold alone or in combination with different CaSO4 concentrations into the bone defects. After 7 weeks, we determined the new bone regenerated by micro-CT and histological analysis. In vitro, we evaluated the CaSO4 effects on MSC migration by both wound healing and agarose spot assays. Osteoblastic gene expression after BMP-2 and CaSO4 treatment was also evaluated by qPCR. Results CaSO4 increased MSC migration and bone formation in a concentration-dependent manner. Micro-CT analysis showed that the addition of CaSO4 significantly enhanced bone regeneration compared to the scaffold alone. The histological evaluation confirmed an increased number of endogenous cells recruited into the cell-free CaSO4-containing scaffolds. Furthermore, MSC migration in vitro and active AKT levels were attenuated when CaSO4 and BMP-2 were in combination. Addition of LY294002 and Wortmannin abrogated the CaSO4 effects on MSC migration. Conclusions Specific CaSO4 concentrations induce bone regeneration of calvarial defects in part by acting on the host’s undifferentiated MSCs and promoting their migration. Progenitor cell recruitment is followed by a gradual increment in osteoblast gene expression. Moreover, CaSO4 regulates BMP-2-induced

  19. PDX1, Neurogenin-3, and MAFA: critical transcription regulators for beta cell development and regeneration

    Yaxi Zhu

    2017-11-01

    Full Text Available Abstract Transcription factors regulate gene expression through binding to specific enhancer sequences. Pancreas/duodenum homeobox protein 1 (PDX1, Neurogenin-3 (NEUROG3, and V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MAFA are transcription factors critical for beta cell development and maturation. NEUROG3 is expressed in endocrine progenitor cells and controls islet differentiation and regeneration. PDX1 is essential for the development of pancreatic exocrine and endocrine cells including beta cells. PDX1 also binds to the regulatory elements and increases insulin gene transcription. Likewise, MAFA binds to the enhancer/promoter region of the insulin gene and drives insulin expression in response to glucose. In addition to those natural roles in beta cell development and maturation, ectopic expression of PDX1, NEUROG3, and/or MAFA has been successfully used to reprogram various cell types into insulin-producing cells in vitro and in vivo, such as pancreatic exocrine cells, hepatocytes, and pluripotent stem cells. Here, we review biological properties of PDX1, NEUROG3, and MAFA, and their applications and limitations for beta cell regenerative approaches. The primary source literature for this review was acquired using a PubMed search for articles published between 1990 and 2017. Search terms include diabetes, insulin, trans-differentiation, stem cells, and regenerative medicine.

  20. Effect of concentrated growth factor combined with guided bone regeneration on cell proliferation and bone resorption in patients with severe periodontitis

    Qiang Gao

    2017-10-01

    Full Text Available Objective: To study the effect of concentrated growth factor (CGF combined with guided bone regeneration on cell proliferation and bone resorption in patients with severe periodontitis. Methods: Patients with severe periodontitis who were treated in Stomatology Department of Shenmu Hospital between May 2014 and February 2017 were selected as the research subjects and randomly divided into two groups, surgery + CGF group received concentrated growth factor combined with guided bone regeneration, and pure surgery group received guided bone regeneration. The contents of inflammatory response, cell proliferation and bone resorption markers in gingival crevicular fluid were determined 1 week after treatment. Results: 1 week after treatment, HMGB1, ICAM1, E-selectin, Smac, FasL, Caspase-8, Caspase-9, Caspase-3, RANKL and NTX contents in gingival crevicular fluid of surgery + CGF group were significantly lower than those of pure surgery group while PD-L1, hBD-3, Wnt3a, BGP and OPG contents were significantly higher than those of pure surgery group. Conclusion: Concentrated growth factor combined with guided bone regeneration for severe periodontitis can inhibit inflammatory response, apoptosis and bone resorption, which is beneficial to the reconstruction of periodontal tissue.

  1. Effects of Human Mesenchymal Stem Cells Isolated from Wharton's Jelly of the Umbilical Cord and Conditioned Media on Skeletal Muscle Regeneration Using a Myectomy Model.

    Pereira, T; Armada-da Silva, P A S; Amorim, I; Rêma, A; Caseiro, A R; Gärtner, A; Rodrigues, M; Lopes, M A; Bártolo, P J; Santos, J D; Luís, A L; Maurício, A C

    2014-01-01

    Skeletal muscle has good regenerative capacity, but the extent of muscle injury and the developed fibrosis might prevent complete regeneration. The in vivo application of human mesenchymal stem cells (HMSCs) of the umbilical cord and the conditioned media (CM) where the HMSCs were cultured and expanded, associated with different vehicles to induce muscle regeneration, was evaluated in a rat myectomy model. Two commercially available vehicles and a spherical hydrogel developed by our research group were used. The treated groups obtained interesting results in terms of muscle regeneration, both in the histological and in the functional assessments. A less evident scar tissue, demonstrated by collagen type I quantification, was present in the muscles treated with HMSCs or their CM. In terms of the histological evaluation performed by ISO 10993-6 scoring, it was observed that HMSCs apparently have a long-term negative effect, since the groups treated with CM presented better scores. CM could be considered an alternative to the in vivo transplantation of these cells, as it can benefit from the local tissue response to secreted molecules with similar results in terms of muscular regeneration. Searching for an optimal vehicle might be the key point in the future of skeletal muscle tissue engineering.

  2. Do cell based tissue engineering products for meniscus regeneration influence vascularization?

    Koch, Matthias; Ehrenreich, Tobias; Koehl, Gudrun; Pattappa, Girish; Pfeifer, Christian; Loibl, Markus; Müller, Michael; Nerlich, Michael; Angele, Peter; Zellner, Johannes

    2017-01-01

    Meniscus regeneration is observed within the peripheral, vascularized zone but decreases in the inner two thirds alongside the vascularization. Within this avascular area, cell-based tissue-engineering-approaches appear to be a promising strategy for the treatment of meniscal defects. Evaluation of the angiogenic potential of cell-based tissue-engineering-products for meniscus healing. Evaluation of angiogenesis induced by rabbit meniscus-pellets, meniscus-cells (MC) or mesenchymal stem-cells (MSC) in cell-based tissue-engineering-products within a rabbit meniscus-ring was performed using a transparent dorsal skin fold chamber in nude mice. Observations were undertaken during a 14 days period. Cell preconditioning differed between experimental groups. Immunohistochemical analysis of the regenerated tissue in the meniscus-ring induced by cell loaded composite scaffolds for differentiation and anti-angiogenic factors were performed. Meniscus-pellets and MSC-/MC-based tissue-engineering-products induced angiogenesis. An accelerated vascularization was detected in the group of meniscus-pellets derived from the vascularized zone compared to avascular meniscus-pellets. In terms of cell-based tissue-engineering-products, chondrogenic preconditioning resulted in significantly increased vessel growth. MSC-constructs showed an accelerated angiogenesis. Immunohistochemical evaluation showed a progressive differentiation and lower content for anti-angiogenic endostatin in the precultured group. Preconditioning of MC-/MSC-based tissue-engineering-products is a promising tool to influence the angiogenic potential of tissue-engineering-products and to adapt these properties according to the aimed tissue qualities.

  3. Mesenchymal stem cells and differentiated insulin producing cells are new horizons for pancreatic regeneration in type I diabetes mellitus.

    Domouky, Ayat M; Hegab, Ashraf S; Al-Shahat, Amal; Raafat, Nermin

    2017-06-01

    Diabetes mellitus has become the third human killer following cancer and cardiovascular disease. Millions of patients, often children, suffer from type 1 diabetes (T1D). Stem cells created hopes to regenerate damaged body tissues and restore their function. This work aimed at clarifying and comparing the therapeutic potential of differentiated and non-differentiated mesenchymal stem cells (MSCs) as a new line of therapy for T1D. 40 Female albino rats divided into group I (control): 10 rats and group II (diabetic), III and IV, 10 rats in each, were injected with streptozotocin (50mg/kg body weight). Group III (MSCs) were transplanted with bone marrow derived MSCs from male rats and group IV (IPCs) with differentiated insulin producing cells. Blood and pancreatic tissue samples were taken from all rats for biochemical and histological studies. MSCs reduced hyperglycemia in diabetic rats on day 15 while IPCs normalizes blood glucose level on day 7. Histological and morphometric analysis of pancreas of experimental diabetic rats showed improvement in MSCs-treated group but in IPCs-treated group, β-cells insulin immunoreactions were obviously returned to normal, with normal distribution of β-cells in the center and other cells at the periphery. Meanwhile, most of the pathological lesions were still detected in diabetic rats. MSCs transplantation can reduce blood glucose level in recipient diabetic rats. IPCs initiate endogenous pancreatic regeneration by neogenesis of islets. IPCs are better than MSCs in regeneration of β-cells. So, IPCs therapy can be considered clinically to offer a hope for patients suffering from T1D. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Spatio-temporal neural stem cell behavior that leads to both perfect and imperfect structural brain regeneration in adult newts.

    Urata, Yuko; Yamashita, Wataru; Inoue, Takeshi; Agata, Kiyokazu

    2018-06-14

    Adult newts can regenerate large parts of their brain from adult neural stem cells (NSCs), but how adult NSCs reorganize brain structures during regeneration remains unclear. In development, elaborate brain structures are produced under broadly coordinated regulations of embryonic NSCs in the neural tube, whereas brain regeneration entails exquisite control of the reestablishment of certain brain parts, suggesting a yet-unknown mechanism directs NSCs upon partial brain excision. Here we report that upon one-quarter excision of the adult newt ( Pleurodeles waltl ) mesencephalon, active participation of local NSCs around specific brain subregions' boundaries leads to some imperfect and some perfect brain regeneration along an individual's rostrocaudal axis. Regeneration phenotypes depend on how the wound closing occurs using local NSCs, and perfect regeneration replicates development-like processes but takes more than one year. Our findings indicate that newt brain regeneration is supported by modularity of boundary-domain NSCs with self-organizing ability in neighboring fields. © 2018. Published by The Company of Biologists Ltd.

  5. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

    Askari, Arman T.; Unzek, Samuel; Popovic, Zoran B.; Goldman, Corey K.; Forudi, Farhad; Kiedrowski, Matthew; Rovner, Aleksandr; Ellis, Stephen G.; Thomas, James D.; DiCorleto, Paul E.; hide

    2003-01-01

    BACKGROUND: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. METHODS: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. FINDINGS: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, pcell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

  6. The Use of Endothelial Progenitor Cells for the Regeneration of Musculoskeletal and Neural Tissues

    Naosuke Kamei

    2017-01-01

    Full Text Available Endothelial progenitor cells (EPCs derived from bone marrow and blood can differentiate into endothelial cells and promote neovascularization. In addition, EPCs are a promising cell source for the repair of various types of vascularized tissues and have been used in animal experiments and clinical trials for tissue repair. In this review, we focused on the kinetics of endogenous EPCs during tissue repair and the application of EPCs or stem cell populations containing EPCs for tissue regeneration in musculoskeletal and neural tissues including the bone, skeletal muscle, ligaments, spinal cord, and peripheral nerves. EPCs can be mobilized from bone marrow and recruited to injured tissue to contribute to neovascularization and tissue repair. In addition, EPCs or stem cell populations containing EPCs promote neovascularization and tissue repair through their differentiation to endothelial cells or tissue-specific cells, the upregulation of growth factors, and the induction and activation of endogenous stem cells. Human peripheral blood CD34(+ cells containing EPCs have been used in clinical trials of bone repair. Thus, EPCs are a promising cell source for the treatment of musculoskeletal and neural tissue injury.

  7. Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1

    Zhou, Bo O; Ding, Lei; Morrison, Sean J

    2015-01-01

    Hematopoietic stem cells (HSCs) are maintained by a perivascular niche in bone marrow but it is unclear whether the niche is reciprocally regulated by HSCs. Here, we systematically assessed the expression and function of Angiopoietin-1 (Angpt1) in bone marrow. Angpt1 was not expressed by osteoblasts. Angpt1 was most highly expressed by HSCs, and at lower levels by c-kit+ hematopoietic progenitors, megakaryocytes, and Leptin Receptor+ (LepR+) stromal cells. Global conditional deletion of Angpt1, or deletion from osteoblasts, LepR+ cells, Nes-cre-expressing cells, megakaryocytes, endothelial cells or hematopoietic cells in normal mice did not affect hematopoiesis, HSC maintenance, or HSC quiescence. Deletion of Angpt1 from hematopoietic cells and LepR+ cells had little effect on vasculature or HSC frequency under steady-state conditions but accelerated vascular and hematopoietic recovery after irradiation while increasing vascular leakiness. Hematopoietic stem/progenitor cells and LepR+ stromal cells regulate niche regeneration by secreting Angpt1, reducing vascular leakiness but slowing niche recovery. DOI: http://dx.doi.org/10.7554/eLife.05521.001 PMID:25821987

  8. Hair cell regeneration in the bullfrog vestibular otolith organs following aminoglycoside toxicity

    Baird, Richard A.; Torres, M. A.; Schuff, N. R.

    1994-01-01

    Adult bullfrogs were given single intraotic injections of the aminoglycoside antibiotic gentamicin sulfate and sacrificed at postinjection times ranging from 0.5 to 9 days. The saccular and utricular maculae of normal and injected animals were examined in wholemount and cross-section. Intraotic 200 (mu) M gentamicin concentrations resulted in the uniform destruction of the hair bundles and, at later times, the cell bodies of saccular hair cells. In the utriculus, striolar hair cells were selectively damaged while extrastriolar hair cells were relatively unaffected. Regenerating hair cells, identified in sectioned material by their small cell bodies and short, well-formed hair bundles, were seen in the saccular and utricular maculae as early as 24-48 h postinjection. Immature versions of mature hair cell types in both otolith organs were recognized by the presence of absence of a bulbed kinocilia and the relative lengths of their kinocilia and longest sterocilia. Utricular hair cell types with kinocilia longer than their longest stereocilia were observed at earlier times than hair cell types with shorter kinocilia. In the same sacculus, the hair bundles of gentamicin-treated animals, even at 9 days postinjection, were significantly smaller than those of normal animals. The hair bundles of utricular hair cells, on the other hand, reached full maturity within the same time period.

  9. Regeneration of Optic Nerve

    Kwok-Fai So

    2011-05-01

    Full Text Available The optic nerve is part of the central nervous system (CNS and has a structure similar to other CNS tracts. The axons that form the optic nerve originate in the ganglion cell layer of the retina and extend through the optic tract. As a tissue, the optic nerve has the same organization as the white matter of the brain in regard to its glia. There are three types of glial cells: Oligodendrocytes, astrocytes, and microglia. Little structural and functional regeneration of the CNS takes place spontaneously following injury in adult mammals. In contrast, the ability of the mammalian peripheral nervous system (PNS to regenerate axons after injury is well documented. A number of factors are involved in the lack of CNS regeneration, including: (i the response of neuronal cell bodies against the damage; (ii myelin-mediated inhibition by oligodendrocytes; (iii glial scarring, by astrocytes; (iv macrophage infiltration; and (v insufficient trophic factor support. The fundamental difference in the regenerative capacity between CNS and PNS neuronal cell bodies has been the subject of intensive research. In the CNS the target normally conveys a retrograde trophic signal to the cell body. CNS neurons die because of trophic deprivation. Damage to the optic nerve disconnects the neuronal cell body from its target-derived trophic peptides, leading to the death of retinal ganglion cells. Furthermore, the axontomized neurons become less responsive to the peptide trophic signals they do receive. On the other hand, adult PNS neurons are intrinsically responsive to neurotrophic factors and do not lose trophic responsiveness after axotomy. In this talk different strategies to promote optic-nerve regeneration in adult mammals are reviewed. Much work is still needed to resolve many issues. This is a very important area of neuroregeneration and neuroprotection, as currently there is no cure after traumatic optic nerve injury or retinal disease such as glaucoma, which

  10. Epithelial architectural destruction is necessary for bone marrow derived cell contribution to regenerating prostate epithelium.

    Palapattu, Ganesh S; Meeker, Alan; Harris, Timothy; Collector, Michael I; Sharkis, Saul J; DeMarzo, Angelo M; Warlick, Christopher; Drake, Charles G; Nelson, William G

    2006-08-01

    Using various nonphysiological tissue injury/repair models numerous studies have demonstrated the capacity of bone marrow derived cells to contribute to the repopulation of epithelial tissues following damage. To investigate whether this phenomenon might also occur during periods of physiological tissue degeneration/regeneration we compared the ability of bone marrow derived cells to rejuvenate the prostate gland in mice that were castrated and then later treated with dihydrotestosterone vs mice with prostate epithelium that had been damaged by lytic virus infection. Using allogenic bone marrow grafts from female donor transgenic mice expressing green fluorescent protein transplanted into lethally irradiated males we were able to assess the contributions of bone marrow derived cells to recovery of the prostatic epithelium in 2 distinct systems, including 1) surgical castration followed 1 week later by dihydrotestosterone replacement and 2) intraprostatic viral injection. Eight to 10-week-old male C57/Bl6 mice were distributed among bone marrow donor-->recipient/prostate injury groups, including 5 with C57/Bl6-->C57/Bl6/no injury, 3 with green fluorescent protein-->C57/Bl6/no injury, 3 with green fluorescent protein-->C57/Bl6/vehicle injection, 4 with green fluorescent protein-->C57/Bl6/virus injection and 3 each with green fluorescent protein-->C57/Bl6/castration without and with dihydrotestosterone, respectively. Prostate tissues were harvested 3 weeks after dihydrotestosterone replacement or 14 days following intraprostatic viral injection. Prostate tissue immunofluorescence was performed with antibodies against the epithelial marker cytokeratin 5/8, the hematopoietic marker CD45 and green fluorescent protein. Mice that sustained prostate injury from vaccinia virus infection with concomitant severe inflammation and glandular disruption showed evidence of bone marrow derived cell reconstitution of prostate epithelium, that is approximately 4% of all green

  11. Braking energy regeneration control of a fuel cell hybrid electric bus

    Zhang, Junzhi; Lv, Chen; Qiu, Mingzhe; Li, Yutong; Sun, Dongsheng

    2013-01-01

    Highlights: • A braking energy regeneration system has been designed for a fuel cell bus. • Control strategy coordinating energy efficiency and brake safety is proposed. • The system and control strategy proposed are experimentally verified. • Based on test results, energy efficiency of the FCB is improved greatly. - Abstract: This paper presents the braking energy regeneration control of a fuel cell hybrid electric bus. The configuration of the regenerative braking system based on a pneumatic braking system was proposed. To recapture the braking energy and improve the fuel economy, a control strategy coordinating the regenerative brake and the pneumatic brake was designed and applied in the FCHB. Brake safety was also guaranteed by the control strategy when the bus encounters critical driving situations. Fuel economy tests were carried out under China city bus typical driving cycle. And hardware-in-the-loop tests of the brake safety of the FCHB under proposed control strategy were also accomplished. Test results indicate that the present approach provides an improvement in fuel economy of the fuel cell hybrid electric bus and guarantees the brake safety in the meantime

  12. Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental glomerulosclerosis

    Eng, Diana G.; Sunseri, Maria W.; Kaverina, Natalya; Roeder, Sebastian S.; Pippin, Jeffrey W.; Shankland, Stuart J.

    2015-01-01

    Since adult podocytes cannot adequately proliferate following depletion in disease states there has been interest in the potential role of progenitors in podocyte repair and regeneration. To determine if parietal epithelial cells (PECs) can serve as adult podocyte progenitors following disease-induced podocyte depletion, PECs were permanently labeled in adult PECrtTA/LC1/R26 reporter mice. In normal mice, labeled PECs were confined to Bowman's capsule, while in disease (cytotoxic sheep anti-podocyte antibody), labeled PECs were found in the glomerular tuft in progressively higher numbers by days 7, 14 and 28. Early in disease, the majority of PECs in the tuft co-expressed CD44. By day 28, when podocyte numbers were significantly higher and disease severity was significantly lower, the majority of labeled PECs co-expressed podocyte proteins but not CD44. Neither labeled PECs on the tuft, nor podocytes stained for the proliferation marker BrdU. The de novo expression of phospho-ERK colocalized to CD44 expressing PECs, but not to PECs expressing podocyte markers. Thus, in a mouse model of focal segmental glomerulosclerosis typified by abrupt podocyte depletion followed by regeneration, PECs undergo two phenotypic changes once they migrate to the glomerular tuft. Initially these cells are predominantly activated CD44 expressing cells coinciding with glomerulosclerosis, and later they predominantly exhibit a podocyte phenotype which is likely reparative. PMID:25993321

  13. The direct cytotoxic effects of medicaments used in endodontic regeneration on human dental pulp cells.

    Labban, Nawaf; Yassen, Ghaeth H; Windsor, L Jack; Platt, Jeffrey A

    2014-12-01

    The purpose of this in vitro study was to evaluate the effects of intracanal medicaments commonly used in endodontic regeneration on the survival of human dental pulp cells (DPCs). DPCs were cultured and exposed to either no medicament treatment or low concentrations (0.3-5 mg ml(-1) ) of calcium hydroxide [Ca(OH)2 ], triple antibiotic paste (TAP), or double antibiotic paste (DAP) for 3 days. After that, toxicity to the DPCs was determined by lactate dehydrogenase activity assays (LDH) and cell proliferation was measured by colorimetric assays (WST-1). Two-way anova followed by Fisher's protected least significant differences was used for statistical analyses (α = 0.05). The group-by-concentration interactions were significant for the LDH and WST-1 assays (P medicaments tested in this study were not cytotoxic in cultured cells. However, these concentrations are much lower than the concentrations that have been advocated in endodontic regeneration. Furthermore, the negative effects of TAP on DPCs were detected at lower concentrations by using the WST-1 assays than by measuring the LDH release. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental glomerulosclerosis.

    Eng, Diana G; Sunseri, Maria W; Kaverina, Natalya V; Roeder, Sebastian S; Pippin, Jeffrey W; Shankland, Stuart J

    2015-11-01

    As adult podocytes cannot adequately proliferate following depletion in disease states, there has been interest in the potential role of progenitors in podocyte repair and regeneration. To determine whether parietal epithelial cells (PECs) can serve as adult podocyte progenitors following disease-induced podocyte depletion, PECs were permanently labeled in adult PEC-rtTA/LC1/R26 reporter mice. In normal mice, labeled PECs were confined to Bowman's capsule, whereas in disease (cytotoxic sheep anti-podocyte antibody) labeled PECs were found in the glomerular tuft in progressively higher numbers by days 7, 14, and 28. Early in disease, the majority of PECs in the tuft coexpressed CD44. By day 28, when podocyte numbers were significantly higher and disease severity was significantly lower, the majority of labeled PECs coexpressed podocyte proteins but not CD44. Neither labeled PECs on the tuft nor podocytes stained for the proliferation marker BrdU. The de novo expression of phospho-ERK colocalized to CD44 expressing PECs, but not to PECs expressing podocyte markers. Thus, in a mouse model of focal segmental glomerulosclerosis typified by abrupt podocyte depletion followed by regeneration, PECs undergo two phenotypic changes once they migrate to the glomerular tuft. Initially these cells are predominantly activated CD44 expressing cells coinciding with glomerulosclerosis, and later they predominantly exhibit a podocyte phenotype, which is likely reparative.

  15. Regeneration of Achilles' tendon: the role of dynamic stimulation for enhanced cell proliferation and mechanical properties.

    Lee, Jongman; Guarino, Vincenzo; Gloria, Antonio; Ambrosio, Luigi; Tae, Giyoong; Kim, Young Ha; Jung, Youngmee; Kim, Sang-Heon; Kim, Soo Hyun

    2010-01-01

    The tissue engineering of tendon was studied using highly elastic poly(L-lactide-co-epsilon-caprolactone) (PLCL) scaffolds and focusing on the effect of dynamic tensile stimulation. Tenocytes from rabbit Achilles tendon were seeded (1.0 x 10(6) cells/scaffold) onto porous PLCL scaffolds and cultured for periods of 2 weeks and 4 weeks. This was performed in a static system and also in a bioreactor equipped with tensile modulation which mimicked the environmental surroundings of tendons with respect to tensile extension. The degradation of the polymeric scaffolds during the culture was relatively slow. However, there was an indication that cells accelerated the degradation of PLCL scaffolds. The scaffold/cell adducts from the static culture exhibited inferior strength (at 2 weeks 350 kPa, 4 weeks 300 kPa) compared to the control without cells (at 2 weeks 460 kPa, 4 weeks 340 kPa), indicating that the cells contributed to the enhanced degradation. On the contrary, the corresponding values of the adducts from the dynamic culture (at 2 weeks 430 kPa, 4 weeks 370 kPa) were similar to, or higher than, those from the control. This could be explained by the increased quantity of cells and neo-tissues in the case of dynamic culture compensating for the loss in tensile strength. Compared with static and dynamic culture conditions, mechanical stimulation played a crucial role in the regeneration of tendon tissue. In the case of the dynamic culture system, cell proliferation was enhanced and secretion of collagen type I was increased, as evidenced by DNA assay and histological and immunofluorescence analysis. Thus, tendon regeneration, indicated by improved mechanical and biological properties, was demonstrated, confirming the effect of mechanical stimulation. It could be concluded that the dynamic tensile stimulation appeared to be an essential factor in tendon/ligament tissue engineering, and that elastic PLCL co-polymers could be very beneficial in this process.

  16. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure

    Honglei eWeng

    2015-06-01

    Full Text Available Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called second pathway of liver regeneration. The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin.

  17. Two sides of one coin: massive hepatic necrosis and progenitor cell-mediated regeneration in acute liver failure.

    Weng, Hong-Lei; Cai, Xiaobo; Yuan, Xiaodong; Liebe, Roman; Dooley, Steven; Li, Hai; Wang, Tai-Ling

    2015-01-01

    Massive hepatic necrosis is a key event underlying acute liver failure, a serious clinical syndrome with high mortality. Massive hepatic necrosis in acute liver failure has unique pathophysiological characteristics including extremely rapid parenchymal cell death and removal. On the other hand, massive necrosis rapidly induces the activation of liver progenitor cells, the so-called "second pathway of liver regeneration." The final clinical outcome of acute liver failure depends on whether liver progenitor cell-mediated regeneration can efficiently restore parenchymal mass and function within a short time. This review summarizes the current knowledge regarding massive hepatic necrosis and liver progenitor cell-mediated regeneration in patients with acute liver failure, the two sides of one coin.

  18. Regeneration of hemopoietic precursor cells in spleen organ cultures from irradiated mice: influence of genotype of cells injected and of the spleen microenvironment

    von Melchner, H.; Lieschke, G.J.

    1981-01-01

    The regeneration of hemopoietic precursor cells (colony-forming cells, CFC) was monitored in spleen organ cultures from lethally irradiated mice injected with 10(7) normal syngeneic or allogeneic bone marrow cells. The important role of the microenvironment in supporting hemopoiesis was confirmed by the failure of mutant S1/S1d spleens to support CFC regeneration in organ cultures. However, the extent and quality of the CFC regeneration was clearly dependent on the genetic properties of the injected cells. Evidence for this was obtained from the regeneration patterns of various CFC types in organ cultured spleens derived from different mouse donor-recipient strain combinations (CBA/CBA, CBA/C57BL, CBA/BALB/c, C57BL/C57BL, C57BL/CBA, C57BL/BALB/c) that maintained the differences in the bone marrow frequency of various CFC types characteristic of the donor strain

  19. Trophic Effects and Regenerative Potential of Mobilized Mesenchymal Stem Cells From Bone Marrow and Adipose Tissue as Alternative Cell Sources for Pulp/Dentin Regeneration.

    Murakami, Masashi; Hayashi, Yuki; Iohara, Koichiro; Osako, Yohei; Hirose, Yujiro; Nakashima, Misako

    2015-01-01

    Dental pulp stem cell (DPSC) subsets mobilized by granulocyte-colony-stimulating factor (G-CSF) are safe and efficacious for complete pulp regeneration. The supply of autologous pulp tissue, however, is very limited in the aged. Therefore, alternative sources of mesenchymal stem/progenitor cells (MSCs) are needed for the cell therapy. In this study, DPSCs, bone marrow (BM), and adipose tissue (AD)-derived stem cells of the same individual dog were isolated using G-CSF-induced mobilization (MDPSCs, MBMSCs, and MADSCs). The positive rates of CXCR4 and G-CSFR in MDPSCs were similar to MADSCs and were significantly higher than those in MBMSCs. Trophic effects of MDPSCs on angiogenesis, neurite extension, migration, and antiapoptosis were higher than those of MBMSCs and MADSCs. Pulp-like loose connective tissues were regenerated in all three MSC transplantations. Significantly higher volume of regenerated pulp and higher density of vascularization and innervation were observed in response to MDPSCs compared to MBMSC and MADSC transplantation. Collagenous matrix containing dentin sialophosphoprotein (DSPP)-positive odontoblast-like cells was the highest in MBMSCs and significantly higher in MADSCs compared to MDPSCs. MBMSCs and MADSCs, therefore, have potential for pulp regeneration, although the volume of regenerated pulp tissue, angiogenesis, and reinnervation, were less. Thus, in conclusion, an alternative cell source for dental pulp/dentin regeneration are stem cells from BM and AD tissue.

  20. Strategies for Controlled Delivery of Growth Factors and Cells for Bone Regeneration

    Vo, Tiffany N.; Kasper, F. Kurtis; Mikos, Antonios G.

    2012-01-01

    The controlled delivery of growth factors and cells within biomaterial carriers can enhance and accelerate functional bone formation. The carrier system can be designed with preprogrammed release kinetics to deliver bioactive molecules in a localized, spatiotemporal manner most similar to the natural wound healing process. The carrier can also act as an extracellular matrix-mimicking substrate for promoting osteoprogenitor cellular infiltration and proliferation for integrative tissue repair. This review discusses the role of various regenerative factors involved in bone healing and their appropriate combinations with different delivery systems for augmenting bone regeneration. The general requirements of protein, cell and gene therapy are described, with elaboration on how the selection of materials, configurations and processing affects growth factor and cell delivery and regenerative efficacy in both in vitro and in vivo applications for bone tissue engineering. PMID:22342771

  1. Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration.

    Glaser, Talita; Cappellari, Angélica Regina; Pillat, Micheli Mainardi; Iser, Isabele Cristiana; Wink, Márcia Rosângela; Battastini, Ana Maria Oliveira; Ulrich, Henning

    2012-09-01

    Replacement of lost or dysfunctional tissues by stem cells has recently raised many investigations on therapeutic applications. Purinergic signaling has been shown to regulate proliferation, differentiation, cell death, and successful engraftment of stem cells originated from diverse origins. Adenosine triphosphate release occurs in a controlled way by exocytosis, transporters, and lysosomes or in large amounts from damaged cells, which is then subsequently degraded into adenosine. Paracrine and autocrine mechanisms induced by immune responses present critical factors for the success of stem cell therapy. While P1 receptors generally exert beneficial effects including anti-inflammatory activity, P2 receptor-mediated actions depend on the subtype of stimulated receptors and localization of tissue repair. Pro-inflammatory actions and excitatory tissue damages mainly result from P2X7 receptor activation, while other purinergic receptor subtypes participate in proliferation and differentiation, thereby providing adequate niches for stem cell engraftment and novel mechanisms for cell therapy and endogenous tissue repair. Therapeutic applications based on regulation of purinergic signaling are foreseen for kidney and heart muscle regeneration, Clara-like cell replacement for pulmonary and bronchial epithelial cells as well as for induction of neurogenesis in case of neurodegenerative diseases.

  2. Reduce, reuse, recycle - Developmental signals in spinal cord regeneration.

    Cardozo, Marcos Julian; Mysiak, Karolina S; Becker, Thomas; Becker, Catherina G

    2017-12-01

    Anamniotes, fishes and amphibians, have the capacity to regenerate spinal cord tissue after injury, generating new neurons that mature and integrate into the spinal circuitry. Elucidating the molecular signals that promote this regeneration is a fundamental question in regeneration research. Model systems, such as salamanders and larval and adult zebrafish are used to analyse successful regeneration. This shows that many developmental signals, such as Notch, Hedgehog (Hh), Bone Morphogenetic Protein (BMP), Wnt, Fibroblast Growth Factor (FGF), Retinoic Acid (RA) and neurotransmitters are redeployed during regeneration and activate resident spinal progenitor cells. Here we compare the roles of these signals in spinal cord development and regeneration of the much larger and fully patterned adult spinal cord. Understanding how developmental signalling systems are reactivated in successfully regenerating species may ultimately lead to ways to reactivate similar systems in mammalian progenitor cells, which do not show neurogenesis after spinal injury. Copyright © 2017. Published by Elsevier Inc.

  3. Application of Induced Pluripotent Stem Cells Reprogrammed from Dental Pulp Cells: a Novel Approach for Tooth Regeneration

    Xiaoyan Zhou

    2011-03-01

    Full Text Available Introduction: Candidate human dental stem/progenitor cells have been isolated and charac-terized from dental tissues and shown to hold the capability to differentiate into tooth-generating cells. However, ad-vances in engineering a whole tooth by these stem cells are hindered by various factors, such as the poor availability of human primitive tooth bud stem cells, difficulties in isolating and purifying dental mesenchymal stem cells and ethical controversies when using embryonic oral epithelium. As a result it is meaningful to find other autologous dental cells for the purpose of reconstructing a tooth.The hypothesis: Previous studies demonstrated that somatic cells can be reprogrammed into induced pluripotent stem cells by ex-ogenous expression Oct-4 and Sox-2. On the basis of these findings we can reasonably hypothesize that when transfected with specific transcription factors Oct-4 and Sox-2, dental pulp cells, the main cell in pulp, could also be reprogrammed into induced pluripotent stem cells, which are considered to be of best potential to regenerate a whole tooth. Evaluation of the hypothesis: After transfection with Oct-4 and Sox-2 into human dental pulp cells, the positive colonies are isolated and then identified according to the characteristics of iPS cells. These cells are further investigated the capability in differentiating into ameloblasts and odontoblasts and finally seeded onto the sur-face of a tooth-shaped biodegradable polymer scaffold to detect the ability of constructing a bioengineered tooth.

  4. The Satellite Cell in Male and Female, Developing and Adult Mouse Muscle: Distinct Stem Cells for Growth and Regeneration

    Neal, Alice; Boldrin, Luisa; Morgan, Jennifer Elizabeth

    2012-01-01

    Satellite cells are myogenic cells found between the basal lamina and the sarcolemma of the muscle fibre. Satellite cells are the source of new myofibres; as such, satellite cell transplantation holds promise as a treatment for muscular dystrophies. We have investigated age and sex differences between mouse satellite cells in vitro and assessed the importance of these factors as mediators of donor cell engraftment in an in vivo model of satellite cell transplantation. We found that satellite cell numbers are increased in growing compared to adult and in male compared to female adult mice. We saw no difference in the expression of the myogenic regulatory factors between male and female mice, but distinct profiles were observed according to developmental stage. We show that, in contrast to adult mice, the majority of satellite cells from two week old mice are proliferating to facilitate myofibre growth; however a small proportion of these cells are quiescent and not contributing to this growth programme. Despite observed changes in satellite cell populations, there is no difference in engraftment efficiency either between satellite cells derived from adult or pre-weaned donor mice, male or female donor cells, or between male and female host muscle environments. We suggest there exist two distinct satellite cell populations: one for muscle growth and maintenance and one for muscle regeneration. PMID:22662253

  5. Stress responsive miR-31 is a major modulator of mouse intestinal stem cells during regeneration and tumorigenesis.

    Tian, Yuhua; Ma, Xianghui; Lv, Cong; Sheng, Xiaole; Li, Xiang; Zhao, Ran; Song, Yongli; Andl, Thomas; Plikus, Maksim V; Sun, Jinyue; Ren, Fazheng; Shuai, Jianwei; Lengner, Christopher J; Cui, Wei; Yu, Zhengquan

    2017-09-05

    Intestinal regeneration and tumorigenesis are believed to be driven by intestinal stem cells (ISCs). Elucidating mechanisms underlying ISC activation during regeneration and tumorigenesis can help uncover the underlying principles of intestinal homeostasis and disease including colorectal cancer. Here we show that miR-31 drives ISC proliferation, and protects ISCs against apoptosis, both during homeostasis and regeneration in response to ionizing radiation injury. Furthermore, miR-31 has oncogenic properties, promoting intestinal tumorigenesis. Mechanistically, miR-31 acts to balance input from Wnt, BMP, TGFβ signals to coordinate control of intestinal homeostasis, regeneration and tumorigenesis. We further find that miR-31 is regulated by the STAT3 signaling pathway in response to radiation injury. These findings identify miR-31 as a critical modulator of ISC biology, and a potential therapeutic target for a broad range of intestinal regenerative disorders and cancers.

  6. Hydrostatic pressure in combination with topographical cues affects the fate of bone marrow-derived human mesenchymal stem cells for bone tissue regeneration.

    Reinwald, Yvonne; El Haj, Alicia J

    2018-03-01

    Topographical and mechanical cues are vital for cell fate, tissue development in vivo, and to mimic the native cell growth environment in vitro. To date, the combinatory effect of mechanical and topographical cues as not been thoroughly investigated. This study investigates the effect of PCL nanofiber alignment and hydrostatic pressure on stem cell differentiation for bone tissue regeneration. Bone marrow-derived human mesenchymal stem cells were seeded onto standard tissue culture plastic and electrospun random and aligned nanofibers. These substrates were either cultured statically or subjected to intermittent hydrostatic pressure at 270 kPa, 1 Hz for 60 min daily over 21 days in osteogenic medium. Data revealed higher cell metabolic activities for all mechanically stimulated cell culture formats compared with non-stimulated controls; and random fibers compared with aligned fibers. Fiber orientation influenced cell morphology and patterns of calcium deposition. Significant up-regulation of Collagen-I, ALP, and Runx-2 were observed for random and aligned fibers following mechanical stimulation; highest levels of osteogenic markers were expressed when hydrostatic pressure was applied to random fibers. These results indicate that fiber alignment and hydrostatic pressure direct stem cell fate and are important stimulus for tissue regeneration. © 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: A: 629-640, 2018. © 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc.

  7. Influence of microgravity on root-cap regeneration and the structure of columella cells in Zea mays

    Moore, R.; McClelen, C. E.; Fondren, W. M.; Wang, C. L.

    1987-01-01

    We launched imbibed seeds and seedlings of Zea mays into outer space aboard the space shuttle Columbia to determine the influence of microgravity on 1) root-cap regeneration, and 2) the distribution of amyloplasts and endoplasmic reticulum (ER) in the putative statocytes (i.e., columella cells) of roots. Decapped roots grown on Earth completely regenerated their caps within 4.8 days after decapping, while those grown in microgravity did not regenerate caps. In Earth-grown seedlings, the ER was localized primarily along the periphery of columella cells, and amyloplasts sedimented in response to gravity to the lower sides of the cells. Seeds germinated on Earth and subsequently launched into outer space had a distribution of ER in columella cells similar to that of Earth-grown controls, but amyloplasts were distributed throughout the cells. Seeds germinated in outer space were characterized by the presence of spherical and ellipsoidal masses of ER and randomly distributed amyloplasts in their columella cells. These results indicate that 1) gravity is necessary for regeneration of the root cap, 2) columella cells can maintain their characteristic distribution of ER in microgravity only if they are exposed previously to gravity, and 3) gravity is necessary to distribute the ER in columella cells of this cultivar of Z. mays.

  8. Cell kinetics during regeneration in the sponge Halisarca caerulea: how local is the response to tissue damage?

    Alexander, B.E.; Achlatis, M.; Osinga, R.; van der Geest, H.G.; Cleutjens, J.P.M.; Schutte, B.; de Goeij, J.M.

    2015-01-01

    Sponges have a remarkable capacity to rapidly regenerate in response to wound infliction. In addition, sponges rapidly renew their filter systems (choanocytes) to maintain a healthy population of cells. This study describes the cell kinetics of choanocytes in the encrusting reef sponge Halisarca

  9. Rhombicuboctahedron unit cell based scaffolds for bone regeneration: geometry optimization with a mechanobiology - driven algorithm.

    Boccaccio, Antonio; Fiorentino, Michele; Uva, Antonio E; Laghetti, Luca N; Monno, Giuseppe

    2018-02-01

    In a context more and more oriented towards customized medical solutions, we propose a mechanobiology-driven algorithm to determine the optimal geometry of scaffolds for bone regeneration that is the most suited to specific boundary and loading conditions. In spite of the huge number of articles investigating different unit cells for porous biomaterials, no studies are reported in the literature that optimize the geometric parameters of such unit cells based on mechanobiological criteria. Parametric finite element models of scaffolds with rhombicuboctahedron unit cell were developed and incorporated into an optimization algorithm that combines them with a computational mechanobiological model. The algorithm perturbs iteratively the geometry of the unit cell until the best scaffold geometry is identified, i.e. the geometry that allows to maximize the formation of bone. Performances of scaffolds with rhombicuboctahedron unit cell were compared with those of other scaffolds with hexahedron unit cells. We found that scaffolds with rhombicuboctahedron unit cell are particularly suited for supporting medium-low loads, while, for higher loads, scaffolds with hexahedron unit cells are preferable. The proposed algorithm can guide the orthopaedic/surgeon in the choice of the best scaffold to be implanted in a patient-specific anatomic region. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Cell-State Transitions Regulated by SLUG Are Critical for Tissue Regeneration and Tumor Initiation

    Sarah Phillips

    2014-05-01

    Full Text Available Perturbations in stem cell activity and differentiation can lead to developmental defects and cancer. We use an approach involving a quantitative model of cell-state transitions in vitro to gain insights into how SLUG/SNAI2, a key developmental transcription factor, modulates mammary epithelial stem cell activity and differentiation in vivo. In the absence of SLUG, stem cells fail to transition into basal progenitor cells, while existing basal progenitor cells undergo luminal differentiation; together, these changes result in abnormal mammary architecture and defects in tissue function. Furthermore, we show that in the absence of SLUG, mammary stem cell activity necessary for tissue regeneration and cancer initiation is lost. Mechanistically, SLUG regulates differentiation and cellular plasticity by recruiting the chromatin modifier lysine-specific demethylase 1 (LSD1 to promoters of lineage-specific genes to repress transcription. Together, these results demonstrate that SLUG plays a dual role in repressing luminal epithelial differentiation while unlocking stem cell transitions necessary for tumorigenesis.

  11. Phosphatase of Regenerating Liver-3 Promotes Motility and Metastasis of Mouse Melanoma Cells

    Wu, Xiaopeng; Zeng, Hu; Zhang, Xianming; Zhao, Ying; Sha, Haibo; Ge, Xiaomei; Zhang, Minyue; Gao, Xiang; Xu, Qiang

    2004-01-01

    Recent reports suggested that phosphatase of regenerating liver (PRL)-3 might be involved in colorectal carcinoma metastasis with an unknown mechanism. Here we demonstrated that PRL-3 expression was up-regulated in human liver carcinoma compared with normal liver. PRL-3 was also highly expressed in metastatic melanoma B16-BL6 cells but not in its lowly metastatic parental cell line, B16 cells. B16 cells transfected with PRL-3 cDNA displayed morphological transformation from epithelial-like shape to fibroblast-like shape. PRL-3-overexpressed cells showed much higher migratory ability, which could be reversed by specific anti-sense oligodeoxynucleotide and the phosphatase inhibitors sodium orthovanadate or potassium bisperoxo oxovanadate V. Meanwhile, the expression of the catalytically inactive PRL-3 mutations (D72A or C104S) significantly reduced the cell migratory capability. In addition, PRL-3 transfectants demonstrated altered extracellular matrix adhesive property and up-regulated integrin-mediated cell spreading efficiency. Furthermore, we confirmed that PRL-3 could facilitate lung and liver metastasis of B16 cells in an experimental metastasis model in mice, consistent with accelerated proliferation and growth rate both in vitro and in vivo. Together, these observations provide convincing evidence that PRL-3 truly plays a causal role in tumor metastasis. PMID:15161639

  12. Stem cells and related factors involved in facial nerve function regeneration

    Kamil H. Nelke

    2015-09-01

    Full Text Available The facial nerve (VII is one of the most important cranial nerves for head and neck surgeons. Its function is closely related to facial expressions that are individual for every person. After its injury or palsy, its functions can be either impaired or absent. Because of the presence of motor, sensory and parasympathetic fibers, the biology of its repair and function restoration depends on many factors. In order to achieve good outcome, many different therapies can be performed in order to restore as much of the nerve function as possible. When rehabilitation and physiotherapy are not sufficient, additional surgical procedures and therapies are taken into serious consideration. The final outcome of many of them is discussable, depending on nerve damage etiology. Stem cells in facial nerve repair are used, but long-term outcomes and results are still not fully known. In order to understand this therapeutic approach, clinicians and surgeons should understand the immunobiology of nerve repair and regeneration. In this review, potential stem cell usage in facial nerve regeneration procedures is discussed.

  13. Plant regeneration from haploid cell suspension-derived protoplasts of Mediterranean rice (Oryza sativa L. cv. Miara).

    Guiderdoni, E; Chaïr, H

    1992-11-01

    More than 750 plants were regenerated from protoplasts isolated from microspore callus-derived cell suspensions of the Mediterranean japonica rice Miara, using a nurse-feeder technique and N6-based culture medium. The mean plating efficiency and the mean regeneration ability of the protocalluses were 0.5% and 49% respectively. Flow cytometric evaluation of the DNA contents of 7 month old-cell and protoplast suspensions showed that they were still haploid. Contrastingly, the DNA contents of leaf cell nuclei of the regenerated protoclones ranged from 1C to 5C including 60% 2C plants. This was consistent with the morphological type and the fertility of the mature plants. These results and the absence of chimeric plants suggest that polyploidization occurred during the early phase of protoplast culture.

  14. Regeneration of hemopoietic precursor cells in spleen organ cultures from irradiated mice: influence of genotype of cells injected and of the spleen microenvironment

    von Melchner, H.; Lieschke, G.J.

    1981-01-01

    The regeneration of hemopoietic precursor cells was monitored in spleen organ cultures from lethally irradiated mice injected with 10(7) normal syngeneic or allogeneic bone marrow cells. The important role of the microenvironment in supporting hemopoiesis was confirmed by the failure of mutant Sl/Sld spleens to support CFC regeneration in organ cultures. However, the extent and quality of the CFC regeneration was clearly dependent on the genetic properties of the injected cells. Evidence for this was obtained from the regeneration patterns of various CFC types in organ cultured spleens derived from different mouse donor-recipient strain combinations that maintained the differences in the bone marrow frequency of various CFC types characteristic of the donor strain

  15. Cells responding to surface structure of calcium phosphate ceramics for bone regeneration.

    Zhang, Jingwei; Sun, Lanying; Luo, Xiaoman; Barbieri, Davide; de Bruijn, Joost D; van Blitterswijk, Clemens A; Moroni, Lorenzo; Yuan, Huipin

    2017-11-01

    Surface structure largely affects the inductive bone-forming potential of calcium phosphate (CaP) ceramics in ectopic sites and bone regeneration in critical-sized bone defects. Surface-dependent osteogenic differentiation of bone marrow stromal cells (BMSCs) partially explained the improved bone-forming ability of submicron surface structured CaP ceramics. In this study, we investigated the possible influence of surface structure on different bone-related cells, which may potentially participate in the process of improved bone formation in CaP ceramics. Besides BMSCs, the response of human brain vascular pericytes (HBVP), C2C12 (osteogenic inducible cells), MC3T3-E1 (osteogenic precursors), SV-HFO (pre-osteoblasts), MG63 (osteoblasts) and SAOS-2 (mature osteoblasts) to the surface structure was evaluated in terms of cell proliferation, osteogenic differentiation and gene expression. The cells were cultured on tricalcium phosphate (TCP) ceramics with either micron-scaled surface structure (TCP-B) or submicron-scaled surface structure (TCP-S) for up to 14 days, followed by DNA, alkaline phosphatase (ALP) and quantitative polymerase chain reaction gene assays. HBVP were not sensitive to surface structure with respect to cell proliferation and osteogenic differentiation, but had downregulated angiogenesis-related gene expression (i.e. vascular endothelial growth factor) on TCP-S. Without additional osteogenic inducing factors, submicron-scaled surface structure enhanced ALP activity and osteocalcin gene expression of human (h)BMSCs and C2C12 cells, favoured the proliferation of MC3T3-E1, MG63 and SAOS-2, and increased ALP activity of MC3T3-E1 and SV-HFO. The results herein indicate that cells with osteogenic potency (either osteogenic inducible cells or osteogenic cells) could be sensitive to surface structure and responded to osteoinductive submicron-structured CaP ceramics in cell proliferation, ALP production or osteogenic gene expression, which favour bone

  16. Forest Service's Northern Research Station FIA launches 24-state study of forest regeneration

    Will McWilliams; Shawn Lehman; Paul Roth; Jim. Westfall

    2012-01-01

    Inventory foresters often quake when asked to count tree seedlings, because the work is tedious and sometimes means tallying hundreds of stems. They also know that the density and quality of advance regeneration are key to the success of new stand establishment. Seedling counts provide valuable information on regeneration adequacy, forest diversity, wildlife habitat,...

  17. Stem Cell Fate Determination during Development and Regeneration of Ectodermal Organs

    Jiménez-Rojo, Lucía; Granchi, Zoraide; Graf, Daniel; Mitsiadis, Thimios A.

    2012-01-01

    The development of ectoderm-derived appendages results in a large variety of highly specialized organs such as hair follicles, mammary glands, salivary glands, and teeth. Despite varying in number, shape, and function, all these ectodermal organs develop through continuous and reciprocal epithelial–mesenchymal interactions, sharing common morphological and molecular features especially during their embryonic development. Diseases such as ectodermal dysplasias can affect simultaneously these organs, suggesting that they may arise from common multipotent precursors residing in the embryonic ectoderm. During embryogenesis, these putative ectodermal stem cells may adopt different fates and consequently be able to generate a variety of tissue-specific stem cells, which are the sources for the various cell lineages that form the diverse organs. The specification of those common epithelial precursors, as well as their further lineage commitment to tissue-specific stem cells, might be controlled by specific signals. It has been well documented that Notch, Wnt, bone morphogenetic protein, and fibroblast growth factor signaling pathways regulate cell fate decisions during the various stages of ectodermal organ development. However, the in vivo spatial and temporal dynamics of these signaling pathways are not yet well understood. Improving the current knowledge on the mechanisms involved in stem cell fate determination during organogenesis and homeostasis of ectodermal organs is crucial to develop effective stem cell-based therapies in order to regenerate or replace pathological and damaged tissues. PMID:22539926

  18. New perspectives in cell delivery systems for tissue regeneration: natural-derived injectable hydrogels.

    Munarin, Fabiola; Petrini, Paola; Bozzini, Sabrina; Tanzi, Maria Cristina

    2012-09-27

    Natural polymers, because of their biocompatibility, availability, and physico-chemical properties have been the materials of choice for the fabrication of injectable hydrogels for regenerative medicine. In particular, they are appealing materials for delivery systems and provide sustained and controlled release of drugs, proteins, gene, cells, and other active biomolecules immobilized.In this work, the use of hydrogels obtained from natural source polymers as cell delivery systems is discussed. These materials were investigated for the repair of cartilage, bone, adipose tissue, intervertebral disc, neural, and cardiac tissue. Papers from the last ten years were considered, with a particular focus on the advances of the last five years. A critical discussion is centered on new perspectives and challenges in the regeneration of specific tissues, with the aim of highlighting the limits of current systems and possible future advancements.

  19. Circulating endothelial progenitor cells do not contribute to regeneration of endothelium after murine arterial injury

    Hagensen, Mette; Raarup, Merete Krog; Mortensen, Martin Bødtker

    2012-01-01

    into endothelial cells (ECs). We tested this theory in a murine arterial injury model using carotid artery transplants and fluorescent reporter mice. METHODS AND RESULTS: Wire-injured carotid artery segments from wild-type mice were transplanted into TIE2-GFP transgenic mice expressing green fluorescent protein...... (GFP) in ECs. We found that the endothelium regenerated with GFP(+) ECs as a function of time, evolving from the anastomosis sites towards the centre of the transplant. A migration front of ECs at Day 7 was verified by scanning electron microscopy and by bright-field microscopy using recipient TIE2-lac......Z mice with endothelial β-galactosidase expression. These experiments indicated migration of flanking ECs rather than homing of circulating cells as the underlying mechanism. To confirm this, we interposed non-injured wild-type carotid artery segments between the denuded transplant and the TIE2-GFP...

  20. Functional recovery of anterior semicircular canal afferents following hair cell regeneration in birds

    Boyle, Richard; Highstein, Stephen M.; Carey, John P.; Xu, Jinping

    2002-01-01

    Streptomycin sulfate (1.2 g/kg i.m.) was administered for 5 consecutive days to 5-7-day-old white Leghorn chicks; this causes damage to semicircular canal hair cells that ultimately regenerate to reform the sensory epithelium. During the recovery period, electrophysiological recordings were taken sequentially from anterior semicircular canal primary afferents using an indentation stimulus of the canal that has been shown to mimic rotational stimulation. Chicks were assigned to an early (14-18 days; n = 8), intermediate (28-34 days; n = 5), and late (38-58 days; n = 4) period based on days after treatment. Seven untreated chicks, 15-67 days old, provided control data. An absence of background and indent-induced discharge was the prominent feature of afferents in the early period: only "silent" afferents were encountered in 5/8 experiments. In several of these chicks, fascicles of afferent fibers were seen extending up to the epithelium that was void of hair cells, and intra- and extracellular biocytin labeling revealed afferent processes penetrating into the supporting cell layer of the crista. In 3/8 chicks 74 afferents could be characterized, and they significantly differed from controls (n = 130) by having a lower discharge rate and a negligible response to canal stimulation. In the intermediate period there was considerable variability in discharge properties of 121 afferents, but as a whole the number of "silent" fibers in the canal nerve diminished, the background rate increased, and a response to canal stimulation detected. Individually biocytin-labeled afferents had normal-appearing terminal specializations in the sensory epithelium by 28 days poststreptomycin. In the late period, afferents (n = 58) remained significantly different from controls in background discharge properties and response gain. The evidence suggests that a considerable amount of variability exists between chicks in the return of vestibular afferent function following ototoxic injury and

  1. Oral Mucosa Harbors a High Frequency of Endothelial Cells: A Novel Postnatal Cell Source for Angiogenic Regeneration.

    Zhou, Jian; Rogers, Jason H; Lee, Scott H; Sun, DongMing; Yao, Hai; Mao, Jeremy J; Kong, Kimi Y

    2017-01-15

    Endothelial progenitor cells/endothelial cells (EPCs/ECs) have great potential to treat pathological conditions such as cardiac infarction, muscle ischemia, and bone fractures, but isolation of EPC/ECs from existing cell sources is challenging due to their low EC frequency. We have isolated endothelial progenitor (EP)-like cells from rat oral mucosa and characterized their yield, immunophenotype, growth, and in vivo angiogenic potential. The frequency of EP-like cells derived from oral mucosa is thousands of folds higher than EPCs derived from donor-match bone marrow samples. EP-like cells from oral mucosa were positive for EC markers CD31, VE-Cadherin, and VEGFR2. Oral mucosa-derived EP-like cells displayed robust uptake of acetylated low-density lipoprotein and formed stable capillary networks in Matrigel. Subcutaneously implanted oral mucosa-derived EP-like cells anastomosed with host blood vessels, implicating their ability to elicit angiogenesis. Similar to endothelial colony-forming cells, EP-like cells from oral mucosa have a significantly higher proliferative rate than human umbilical vein endothelial cells. These findings identify a putative EPC source that is easily accessible in the oral cavity, potentially from discarded tissue specimens, and yet with robust yield and potency for angiogenesis in tissue and organ regeneration.

  2. Regeneration of the digestive system in the crinoid Himerometra robustipinna occurs by transdifferentiation of neurosecretory-like cells

    Kalacheva, Nadezhda V.; Eliseikina, Marina G.; Frolova, Lidia T.

    2017-01-01

    The structure and regeneration of the digestive system in the crinoid Himerometra robustipinna (Carpenter, 1881) were studied. The gut comprises a spiral tube forming radial lateral processes, which gives it a five-lobed shape. The digestive tube consists of three segments: esophagus, intestine, and rectum. The epithelia of these segments have different cell compositions. Regeneration of the gut after autotomy of the visceral mass progresses very rapidly. Within 6 h after autotomy, an aggregation consisting of amoebocytes, coelomic epithelial cells and juxtaligamental cells (neurosecretory neurons) forms on the inner surface of the skeletal calyx. At 12 h post-autotomy, transdifferentiation of the juxtaligamental cells starts. At 24 h post-autotomy these cells undergo a mesenchymal-epithelial-like transition, resulting in the formation of the luminal epithelium of the gut. Specialization of the intestinal epithelial cells begins on day 2 post-autotomy. At this stage animals acquire the mouth and anal opening. On day 4 post-autotomy the height of both the enterocytes and the visceral mass gradually increases. Proliferation does not play any noticeable role in gut regeneration. The immersion of animals in a 10−7 M solution of colchicine neither stopped formation of the lost structures nor caused accumulation of mitoses in tissues. Weakly EdU-labeled nuclei were observed in the gut only on day 2 post-autotomy and were not detected at later regeneration stages. Single mitotically dividing cells were recorded during the same period. It is concluded that juxtaligamental cells play a major role in gut regeneration in H. robustipinna. The main mechanisms of morphogenesis are cell migration and transdifferentiation. PMID:28753616

  3. Regeneration of the digestive system in the crinoid Himerometra robustipinna occurs by transdifferentiation of neurosecretory-like cells.

    Kalacheva, Nadezhda V; Eliseikina, Marina G; Frolova, Lidia T; Dolmatov, Igor Yu

    2017-01-01

    The structure and regeneration of the digestive system in the crinoid Himerometra robustipinna (Carpenter, 1881) were studied. The gut comprises a spiral tube forming radial lateral processes, which gives it a five-lobed shape. The digestive tube consists of three segments: esophagus, intestine, and rectum. The epithelia of these segments have different cell compositions. Regeneration of the gut after autotomy of the visceral mass progresses very rapidly. Within 6 h after autotomy, an aggregation consisting of amoebocytes, coelomic epithelial cells and juxtaligamental cells (neurosecretory neurons) forms on the inner surface of the skeletal calyx. At 12 h post-autotomy, transdifferentiation of the juxtaligamental cells starts. At 24 h post-autotomy these cells undergo a mesenchymal-epithelial-like transition, resulting in the formation of the luminal epithelium of the gut. Specialization of the intestinal epithelial cells begins on day 2 post-autotomy. At this stage animals acquire the mouth and anal opening. On day 4 post-autotomy the height of both the enterocytes and the visceral mass gradually increases. Proliferation does not play any noticeable role in gut regeneration. The immersion of animals in a 10-7 M solution of colchicine neither stopped formation of the lost structures nor caused accumulation of mitoses in tissues. Weakly EdU-labeled nuclei were observed in the gut only on day 2 post-autotomy and were not detected at later regeneration stages. Single mitotically dividing cells were recorded during the same period. It is concluded that juxtaligamental cells play a major role in gut regeneration in H. robustipinna. The main mechanisms of morphogenesis are cell migration and transdifferentiation.

  4. Hydrostatic pressure in combination with topographical cues affects the fate of bone marrow‐derived human mesenchymal stem cells for bone tissue regeneration

    El Haj, Alicia J.

    2017-01-01

    Abstract Topographical and mechanical cues are vital for cell fate, tissue development in vivo, and to mimic the native cell growth environment in vitro. To date, the combinatory effect of mechanical and topographical cues as not been thoroughly investigated. This study investigates the effect of PCL nanofiber alignment and hydrostatic pressure on stem cell differentiation for bone tissue regeneration. Bone marrow‐derived human mesenchymal stem cells were seeded onto standard tissue culture plastic and electrospun random and aligned nanofibers. These substrates were either cultured statically or subjected to intermittent hydrostatic pressure at 270 kPa, 1 Hz for 60 min daily over 21 days in osteogenic medium. Data revealed higher cell metabolic activities for all mechanically stimulated cell culture formats compared with non‐stimulated controls; and random fibers compared with aligned fibers. Fiber orientation influenced cell morphology and patterns of calcium deposition. Significant up‐regulation of Collagen‐I, ALP, and Runx‐2 were observed for random and aligned fibers following mechanical stimulation; highest levels of osteogenic markers were expressed when hydrostatic pressure was applied to random fibers. These results indicate that fiber alignment and hydrostatic pressure direct stem cell fate and are important stimulus for tissue regeneration. © 2017 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: A: 629–640, 2018. PMID:28984025

  5. Intrathymic radioresistant stem cells follow an IL-2/IL-2R pathway during thymic regeneration after sublethal irradiation

    Zuniga-Pfluecker, J.C.K.; Kruisbeek, A.M.

    1990-01-01

    Sublethally irradiated mice undergo thymic regeneration which follows a phenotypic pattern of events similar to that observed during normal fetal development. Thymic regeneration after irradiation is the product of a limited pool of intrathymic radioresistant stem cells undergoing simultaneous differentiation. We show that in this model of T cell development, thymic regeneration follows a pathway in which the IL-2R is transiently expressed on CD4-/CD8- cells. IL-2R expression occurred during the exponential growth period of thymic regeneration, and IL-2R blocking prevented this explosive growth. Flow cytometry analysis revealed that the IL-2R blockade affected primarily the development of the immature CD3-/CD4-/CD8- (triple negative) cells and their ability to generate CD3+/CD4+/CD8+ or CD3+/CD4+/CD8- and CD3+/CD4-/CD8+ thymocytes. Thus, our findings demonstrate that blocking of the IL-2R resulted in an arrest in proliferation and differentiation by intrathymic radioresistant stem cells, indicating that the IL-2/IL-2R pathway is necessary for the expansion of immature triple negative T cells

  6. Direct Conversion of Human Fibroblasts into Schwann Cells that Facilitate Regeneration of Injured Peripheral Nerve In Vivo.

    Sowa, Yoshihiro; Kishida, Tsunao; Tomita, Koichi; Yamamoto, Kenta; Numajiri, Toshiaki; Mazda, Osam

    2017-04-01

    Schwann cells (SCs) play pivotal roles in the maintenance and regeneration of the peripheral nervous system. Although transplantation of SCs enhances repair of experimentally damaged peripheral and central nerve tissues, it is difficult to prepare a sufficient number of functional SCs for transplantation therapy without causing adverse events for the donor. Here, we generated functional SCs by somatic cell reprogramming procedures and demonstrated their capability to promote peripheral nerve regeneration. Normal human fibroblasts were phenotypically converted into SCs by transducing SOX10 and Krox20 genes followed by culturing for 10 days resulting in approximately 43% directly converted Schwann cells (dSCs). The dSCs expressed SC-specific proteins, secreted neurotrophic factors, and induced neuronal cells to extend neurites. The dSCs also displayed myelin-forming capability both in vitro and in vivo. Moreover, transplantation of the dSCs into the transected sciatic nerve in mice resulted in significantly accelerated regeneration of the nerve and in improved motor function at a level comparable to that with transplantation of the SCs obtained from a peripheral nerve. The dSCs induced by our procedure may be applicable for novel regeneration therapy for not only peripheral nerve injury but also for central nerve damage and for neurodegenerative disorders related to SC dysfunction. Stem Cells Translational Medicine 2017;6:1207-1216. © 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

  7. External fixation of femoral defects in athymic rats: Applications for human stem cell implantation and bone regeneration

    Terasa Foo

    2013-01-01

    Full Text Available An appropriate animal model is critical for the research of stem/progenitor cell therapy and tissue engineering for bone regeneration in vivo. This study reports the design of an external fixator and its application to critical-sized femoral defects in athymic rats. The external fixator consists of clamps and screws that are readily available from hardware stores as well as Kirschner wires. A total of 35 rats underwent application of the external fixator with creation of a 6-mm bone defect in one femur of each animal. This model had been used in several separate studies, including implantation of collagen gel, umbilical cord blood mesenchymal stem cells, endothelial progenitor cells, or bone morphogenetic protein-2. One rat developed fracture at the proximal pin site and two rats developed deep tissue infection. Pin loosening was found in nine rats, but it only led to the failure of external fixation in two animals. In 8 to 10 weeks, various degrees of bone growth in the femoral defects were observed in different study groups, from full repair of the bone defect with bone morphogenetic protein-2 implantation to fibrous nonunion with collagen gel implantation. The external fixator used in these studies provided sufficient mechanical stability to the bone defects and had a comparable complication rate in athymic rats as in immunocompetent rats. The external fixator does not interfere with the natural environment of a bone defect. This model is particularly valuable for investigation of osteogenesis of human stem/progenitor cells in vivo.

  8. A Miniature Swine Model for Stem Cell-Based De Novo Regeneration of Dental Pulp and Dentin-Like Tissue.

    Zhu, Xiaofei; Liu, Jie; Yu, Zongdong; Chen, Chao-An; Aksel, Hacer; Azim, Adham A; Huang, George T-J

    2018-02-01

    The goal of this study was to establish mini-swine as a large animal model for stem cell-based pulp regeneration studies. Swine dental pulp stem cells (sDPSCs) were isolated from mini-swine and characterized in vitro. For in vivo studies, we first employed both ectopic and semi-orthotopic study models using severe combined immunodeficiency mice. One is hydroxyapatite-tricalcium phosphate (HA/TCP) model for pulp-dentin complex formation, and the other is tooth fragment model for complete pulp regeneration with new dentin depositing along the canal walls. We found that sDPSCs are similar to their human counterparts exhibiting mesenchymal stem cell characteristics with ability to form colony forming unit-fibroblastic and odontogenic differentiation potential. sDPSCs formed pulp-dentin complex in the HA/TCP model and showed pulp regeneration capacity in the tooth fragment model. We then tested orthotopic pulp regeneration on mini-swine including the use of multi-rooted teeth. Using autologous sDPSCs carried by hydrogel and transplanted into the mini-swine root canal space, we observed regeneration of vascularized pulp-like tissue with a layer of newly deposited dentin-like (rD) tissue or osteodentin along the canal walls. In some cases, dentin bridge-like structure was observed. Immunohistochemical analysis detected the expression of nestin, dentin sialophosphoprotein, dentin matrix protein 1, and bone sialoprotein in odontoblast-like cells lining against the produced rD. We also tested the use of allogeneic sDPSCs for the same procedures. Similar findings were observed in allogeneic transplantation. This study is the first to show an establishment of mini-swine as a suitable large animal model utilizing multi-rooted teeth for further cell-based pulp regeneration studies.

  9. Biology of teeth and implants: Host factors - pathology, regeneration, and the role of stem cells.

    Eggert, F-Michael; Levin, Liran

    2018-01-01

    In chronic periodontitis and peri-implantitis, cells of the innate and adaptive immune systems are involved directly in the lesions within the tissues of the patient. Absence of a periodontal ligament around implants does not prevent a biologic process similar to that of periodontitis from affecting osseointegration. Our first focus is on factors in the biology of individuals that are responsible for the susceptibility of such individuals to chronic periodontitis and to peri-implantitis. Genetic factors are of significant importance in susceptibility to these diseases. Genetic factors of the host affect the composition of the oral microbiome in the same manner that they influence other microbiomes, such as those of the intestines and of the lungs. Our second focus is on the central role of stem cells in tissue regeneration, in the functioning of innate and adaptive immune systems, and in metabolism of bone. Epithelial cell rests of Malassez (ERM) are stem cells of epithelial origin that maintain the periodontal ligament as well as the cementum and alveolar bone associated with the ligament. The tissue niche within which ERM are found extends into the supracrestal areas of collagen fiber-containing tissues of the gingivae above the bony alveolar crest. Maintenance and regeneration of all periodontal tissues involves the activity of a variety of stem cells. The success of dental implants indicates that important groups of stem cells in the periodontium are active to enable that biologic success. Successful replantation of avulsed teeth and auto-transplantation of teeth is comparable to placing dental implants, and so must also involve periodontal stem cells. Biology of teeth and biology of implants represents the biology of the various stem cells that inhabit specialized niches within the periodontal tissues. Diverse biologic processes must function together successfully to maintain periodontal health. Osseointegration of dental implants does not involve formation of

  10. Cell-seeded polyurethane-fibrin structures – A possible system for intervertebral disc regeneration

    C Mauth

    2009-10-01

    Full Text Available Nowadays, intervertebral disc (IVD degeneration is one of the principal causes of low back pain involving high expense within the health care system. The long-term goal is the development of a medical treatment modality focused on a more biological regeneration of the inner nucleus pulposus (NP. Hence, interest in the endoscopic implantation of an injectable material took center stage in the recent past. We report on the development of a novel polyurethane (PU scaffold as a mechanically stable carrier system for the reimplantation of expanded autologous IVD-derived cells (disc cells to stimulate regenerative processes and restore the chondrocyte-like tissue within the NP. Primary human disc cells were seeded into newly developed PU spheroids which were subsequently encapsulated in fibrin hydrogel. The study aims to analyze adhesion properties, proliferation capacity and phenotypic characterization of these cells. Polymerase chain reaction was carried out to detect the expression of genes specifically expressed by native IVD cells. Biochemical analyses showed an increased DNA content, and a progressive enhancement of total collagen and glycosaminoglycans (GAG was observed during cell culture. The results suggest the synthesis of an appropriate extracellular matrix as well as a stable mRNA expression of chondrogenic and/or NP specific markers. In conclusion, the data presented indicate an alternative medical approach to current treatment options of degenerated IVD tissue.

  11. Cellular reactions of osteoblast-like cells to a novel nanocomposite membrane for guided bone regeneration

    Meng Yao [State Key Laboratory of Oral Diseases, West China Stomatology Hospital, Sichuan University, Chengdu 610041 (China); Department of Orthodontics, West China Stomatology Hospital, Sichuan University, Chengdu 610041 (China); Liu Man [State Key Laboratory of Oral Diseases, West China Stomatology Hospital, Sichuan University, Chengdu 610041 (China); Stomatology Health Care Center, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen 518048 (China); Wang Shaoan [State Key Laboratory of Oral Diseases, West China Stomatology Hospital, Sichuan University, Chengdu 610041 (China); Mo Anchun [State Key Laboratory of Oral Diseases, West China Stomatology Hospital, Sichuan University, Chengdu 610041 (China)], E-mail: moanchun@163.com; Huang, Cui [State Key Laboratory of Oral Diseases, West China Stomatology Hospital, Sichuan University, Chengdu 610041 (China); Zuo Yi; Li Jidong [Research Center for Nano-biomaterials, Sichuan University, Chengdu 610041 (China)

    2008-11-15

    This study investigated the bioactivity and biocompatibility of hydroxyapatite nanoparticles (n-HA)/Polyamide-66 (PA66) nanocomposite membrane and expanded-polytetrafluoroethylene (e-PTFE) membrane (as control) to MG63 osteoblast-like cells. The attachment and proliferation of the cells on the porous surface of nHA/PA66 membrane and the surface of e-PTFE membrane were evaluated by scanning electron microscope (SEM) observation and the MTT assay. The bioactivity of the cells on the surface of the two membranes was evaluated by testing cell viability and alkaline phosphatase (ALP) activities. The results suggested that the bioresponse of MG63 osteoblast-like cells on the porous surface of nHA/PA66 membrane was better than the bioresponse on the opposite surface of e-PTFE membrane. Because of a better cell attachment manner, there is a potential utilization of the guided bone regeneration (GBR) membrane to substitute nHA/PA66 membrane for e-PTFE membra0008.

  12. An update on application of nanotechnology and stem cells in spinal cord injury regeneration.

    Nejati-Koshki, Kazem; Mortazavi, Yousef; Pilehvar-Soltanahmadi, Younes; Sheoran, Sumit; Zarghami, Nosratollah

    2017-06-01

    Spinal cord injury (SCI) is damage to the spinal cord that leads to sudden loss of motor and autonomic function and sensory under the level of the injury. The pathophysiological advancement of SCI is divided into two categories: primary injury and secondary injury. Due to the loss of motor, sensory, or cognitive function, a patient's quality of life is likely reduced and places a great burden on society in order to supply health care costs. Therefore, it is important to develop suitable therapeutic strategies for SCI therapy. Nano biomedical systems and stem cell based therapy have the potential to provide new therapeutic availability and efficacy over conventional medicine. Due to their unique properties, nanomaterials and mesenchymal stem cells can be used to offer efficient treatments. Nanoparticles have a potential to deliver therapeutic molecules to the target tissue of interest, reducing side effects of untargeted therapies in unwanted areas. Mesenchymal stem cells (MSCs) can reduce activating inflammation responses that lead to cell death and promote functional recovery and cell growth. We review recent uses of nanomaterials and stem cells in regeneration of SCI. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  13. Cellular reactions of osteoblast-like cells to a novel nanocomposite membrane for guided bone regeneration

    Meng Yao; Liu Man; Wang Shaoan; Mo Anchun; Huang, Cui; Zuo Yi; Li Jidong

    2008-01-01

    This study investigated the bioactivity and biocompatibility of hydroxyapatite nanoparticles (n-HA)/Polyamide-66 (PA66) nanocomposite membrane and expanded-polytetrafluoroethylene (e-PTFE) membrane (as control) to MG63 osteoblast-like cells. The attachment and proliferation of the cells on the porous surface of nHA/PA66 membrane and the surface of e-PTFE membrane were evaluated by scanning electron microscope (SEM) observation and the MTT assay. The bioactivity of the cells on the surface of the two membranes was evaluated by testing cell viability and alkaline phosphatase (ALP) activities. The results suggested that the bioresponse of MG63 osteoblast-like cells on the porous surface of nHA/PA66 membrane was better than the bioresponse on the opposite surface of e-PTFE membrane. Because of a better cell attachment manner, there is a potential utilization of the guided bone regeneration (GBR) membrane to substitute nHA/PA66 membrane for e-PTFE membrane

  14. Delivery of adipose-derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration.

    Allbright, Kassandra O; Bliley, Jacqueline M; Havis, Emmanuelle; Kim, Deok-Yeol; Dibernardo, Gabriella A; Grybowski, Damian; Waldner, Matthias; James, Isaac B; Sivak, Wesley N; Rubin, J Peter; Marra, Kacey G

    2018-02-06

    Peripheral nerve damage is associated with high long-term morbidity. Because of beneficial secretome, immunomodulatory effects, and ease of clinical translation, transplantation with adipose-derived stem cells (ASC) represents a promising therapeutic modality. Effect of ASC delivery in poloxamer hydrogel was assessed in a rat sciatic nerve model of critical-sized (1.5 cm) peripheral nerve injury. Nerve/muscle unit regeneration was assessed via immunostaining explanted nerve, quantitative polymerase chain reaction (qPCR), and histological analysis of reinnervating gastrocnemius muscle. On the basis of viability data, 10% poloxamer hydrogel was selected for in vivo study. Six weeks after transection and repair, the group treated with poloxamer delivered ASCs demonstrated longest axonal regrowth. The qPCR results indicated that the inclusion of ASCs appeared to result in expression of factors that aid in reinnervating muscle tissue. Delivery of ASCs in poloxamer addresses multiple facets of the complexity of nerve/muscle unit regeneration, representing a promising avenue for further study. Muscle Nerve, 2018. © 2018 Wiley Periodicals, Inc.

  15. Hydrogen Generation in Microbial Reverse-Electrodialysis Electrolysis Cells Using a Heat-Regenerated Salt Solution

    Nam, Joo-Youn

    2012-05-01

    Hydrogen gas can be electrochemically produced in microbial reverse-electrodialysis electrolysis cells (MRECs) using current derived from organic matter and salinity-gradient energy such as river water and seawater solutions. Here, it is shown that ammonium bicarbonate salts, which can be regenerated using low-temperature waste heat, can also produce sufficient voltage for hydrogen gas generation in an MREC. The maximum hydrogen production rate was 1.6 m3 H2/m3·d, with a hydrogen yield of 3.4 mol H2/mol acetate at a salinity ratio of infinite. Energy recovery was 10% based on total energy applied with an energy efficiency of 22% based on the consumed energy in the reactor. The cathode overpotential was dependent on the catholyte (sodium bicarbonate) concentration, but not the salinity ratio, indicating high catholyte conductivity was essential for maximizing hydrogen production rates. The direction of the HC and LC flows (co- or counter-current) did not affect performance in terms of hydrogen gas volume, production rates, or stack voltages. These results show that the MREC can be successfully operated using ammonium bicarbonate salts that can be regenerated using conventional distillation technologies and waste heat making the MREC a useful method for hydrogen gas production from wastes. © 2012 American Chemical Society.

  16. BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs

    Finnson Kenneth

    2010-02-01

    Full Text Available Abstract Background Axolotls have the unique ability, among vertebrates, to perfectly regenerate complex body parts, such as limbs, after amputation. In addition, axolotls pattern developing and regenerating autopods from the anterior to posterior axis instead of posterior to anterior like all tetrapods studied to date. Sonic hedgehog is important in establishing this anterior-posterior axis of limbs in all tetrapods including axolotls. Interestingly, its expression is conserved (to the posterior side of limb buds and blastemas in axolotl limbs as in other tetrapods. It has been suggested that BMP-2 may be the secondary mediator of sonic hedgehog, although there is mounting evidence to the contrary in mice. Since BMP-2 expression is on the anterior portion of developing and regenerating limbs prior to digit patterning, opposite to the expression of sonic hedgehog, we examined whether BMP-2 expression was dependent on sonic hedgehog signaling and whether it affects patterning of the autopod during regeneration. Results The expression of BMP-2 and SOX-9 in developing and regenerating axolotl limbs corresponded to the first digits forming in the anterior portion of the autopods. The inhibition of sonic hedgehog signaling with cyclopamine caused hypomorphic limbs (during development and regeneration but did not affect the expression of BMP-2 and SOX-9. Overexpression of BMP-2 in regenerating limbs caused a loss of digits. Overexpression of Noggin (BMP inhibitor in regenerating limbs also resulted in a loss of digits. Histological analysis indicated that the loss due to BMP-2 overexpression was the result of increased cell condensation and apoptosis while the loss caused by Noggin was due to a decrease in cell division. Conclusion The expression of BMP-2 and its target SOX-9 was independent of sonic hedgehog signaling in developing and regenerating limbs. Their expression correlated with chondrogenesis and the appearance of skeletal elements has

  17. Arabidopsis Regenerating Protoplast: A Powerful Model System for Combining the Proteomics of Cell Wall Proteins and the Visualization of Cell Wall Dynamics

    Yokoyama, Ryusuke; Kuki, Hiroaki; Kuroha, Takeshi; Nishitani, Kazuhiko

    2016-01-01

    The development of a range of sub-proteomic approaches to the plant cell wall has identified many of the cell wall proteins. However, it remains difficult to elucidate the precise biological role of each protein and the cell wall dynamics driven by their actions. The plant protoplast provides an excellent means not only for characterizing cell wall proteins, but also for visualizing the dynamics of cell wall regeneration, during which cell wall proteins are secreted. It therefore offers a uni...

  18. Local delivery of glial cell line-derived neurotrophic factor improves facial nerve regeneration after late repair.

    Barras, Florian M; Kuntzer, Thierry; Zurn, Anne D; Pasche, Philippe

    2009-05-01

    Facial nerve regeneration is limited in some clinical situations: in long grafts, by aged patients, and when the delay between nerve lesion and repair is prolonged. This deficient regeneration is due to the limited number of regenerating nerve fibers, their immaturity and the unresponsiveness of Schwann cells after a long period of denervation. This study proposes to apply glial cell line-derived neurotrophic factor (GDNF) on facial nerve grafts via nerve guidance channels to improve the regeneration. Two situations were evaluated: immediate and delayed grafts (repair 7 months after the lesion). Each group contained three subgroups: a) graft without channel, b) graft with a channel without neurotrophic factor; and c) graft with a GDNF-releasing channel. A functional analysis was performed with clinical observation of facial nerve function, and nerve conduction study at 6 weeks. Histological analysis was performed with the count of number of myelinated fibers within the graft, and distally to the graft. Central evaluation was assessed with Fluoro-Ruby retrograde labeling and Nissl staining. This study showed that GDNF allowed an increase in the number and the maturation of nerve fibers, as well as the number of retrogradely labeled neurons in delayed anastomoses. On the contrary, after immediate repair, the regenerated nerves in the presence of GDNF showed inferior results compared to the other groups. GDNF is a potent neurotrophic factor to improve facial nerve regeneration in grafts performed several months after the nerve lesion. However, GDNF should not be used for immediate repair, as it possibly inhibits the nerve regeneration.

  19. Adipose-Derived Stem Cells Promote Peripheral Nerve Regeneration In Vivo without Differentiation into Schwann-Like Lineage.

    Sowa, Yoshihiro; Kishida, Tsunao; Imura, Tetsuya; Numajiri, Toshiaki; Nishino, Kenichi; Tabata, Yasuhiko; Mazda, Osam

    2016-02-01

    During recent decades, multipotent stem cells were found to reside in the adipose tissue, and these adipose-derived stem cells were shown to play beneficial roles, like those of Schwann cells, in peripheral nerve regeneration. However, it has not been well established whether adipose-derived stem cells offer beneficial effects to peripheral nerve injuries in vivo as Schwann cells do. Furthermore, the in situ survival and differentiation of adipose-derived stem cells after transplantation at the injured peripheral nerve tissue remain to be fully elucidated. Adipose-derived stem cells and Schwann cells were transplanted with gelatin hydrogel tubes at the artificially blunted sciatic nerve lesion in mice. Neuroregenerative abilities of them were comparably estimated. Cre-loxP-mediated fate tracking was performed to visualize survival in vivo of transplanted adipose-derived stem cells and to investigate whether they differentiated into Schwann linage cells at the peripheral nerve injury site. The transplantation of adipose-derived stem cells promoted regeneration of axons, formation of myelin, and restoration of denervation muscle atrophy to levels comparable to those achieved by Schwann cell transplantation. The adipose-derived stem cells survived for at least 4 weeks after transplantation without differentiating into Schwann cells. Transplanted adipose-derived stem cells did not differentiate into Schwann cells but promoted peripheral nerve regeneration at the injured site. The neuroregenerative ability was comparable to that of Schwann cells. Adipose-derived stem cells at an undifferentiated stage may be used as an alternative cell source for autologous cell therapy for patients with peripheral nerve injury.

  20. Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010-2015).

    Singh, Aastha; Singh, Abhishek; Sen, Dwaipayan

    2016-06-04

    Mesenchymal stem cells have been used for cardiovascular regenerative therapy for decades. These cells have been established as one of the potential therapeutic agents, following several tests in animal models and clinical trials. In the process, various sources of mesenchymal stem cells have been identified which help in cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Although mesenchymal cell therapy has achieved considerable admiration, some challenges still remain that need to be overcome in order to establish it as a successful technique. This in-depth review is an attempt to summarize the major sources of mesenchymal stem cells involved in myocardial regeneration, the significant mechanisms involved in the process with a focus on studies (human and animal) conducted in the last 6 years and the challenges that remain to be addressed.

  1. Bone marrow-derived stromal cells are more beneficial cell sources for tooth regeneration compared with adipose-derived stromal cells.

    Ye, Lanfeng; Chen, Lin; Feng, Fan; Cui, Junhui; Li, Kaide; Li, Zhiyong; Liu, Lei

    2015-10-01

    Tooth loss is presently a global epidemic and tooth regeneration is thought to be a feasible and ideal treatment approach. Choice of cell source is a primary concern in tooth regeneration. In this study, the odontogenic differentiation potential of two non-dental-derived stem cells, adipose-derived stromal cells (ADSCs) and bone marrow-derived stromal cells (BMSCs), were evaluated both in vitro and in vivo. ADSCs and BMSCs were induced in vitro in the presence of tooth germ cell-conditioned medium (TGC-CM) prior to implantation into the omentum majus of rats, in combination with inactivated dentin matrix (IDM). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression levels of odontogenic-related genes. Immunofluorescence and immunohistochemical assays were used to detect the protein levels of odontogenic-specific genes, such as DSP and DMP-1 both in vitro and in vivo. The results suggest that both ADSCs and BMSCs have odontogenic differentiation potential. However, the odontogenic potential of BMSCs was greater compared with ADSCs, showing that BMSCs are a more appropriate cell source for tooth regeneration. © 2015 International Federation for Cell Biology.

  2. Conduction of impulses by axons regenerated in a Schwann cell graft in the transected adult rat thoracic spinal cord.

    Pinzon, A; Calancie, B; Oudega, M; Noga, B R

    2001-06-01

    Central nervous system axons regenerate into a Schwann cell implant placed in the transected thoracic spinal cord of an adult rat. The present study was designed to test whether these regenerated axons are capable of conducting action potentials. Following the transection and removal of a 4- to 5-mm segment of the thoracic spinal cord (T8-T9), a polymer guidance channel filled with a mixture of adult rat Schwann cells and Matrigel was grafted into a 4- to 5-mm-long gap in the transected thoracic spinal cord. The two cut ends of the spinal cord were eased into the guidance channel openings. Transected control animals received a channel containing Matrigel only. Three months after implantation, electrophysiological studies were performed. Tungsten microelectrodes were used for monopolar stimulation of regenerated axons within the Schwann cell graft. Glass microelectrodes were used to record responses in the spinal cord rostral to the stimulation site. Evoked responses to electrical stimulation of the axon cable were found in two out of nine Schwann cell-grafted animals. These responses had approximate latencies in the range of those of myelinated axons. No responses were seen in any of the Matrigel-grafted animals. Histological analysis revealed that the two cases that showed evoked potentials had the largest number of myelinated axons present in the cable. This study demonstrates that axons regenerating through Schwann cell grafts in the complete transected spinal cord can produce measurable evoked responses following electrical stimulation. Copyright 2001 Wiley-Liss, Inc.

  3. Tissue regeneration and biomineralization in sea urchins: role of Notch signaling and presence of stem cell markers.

    Helena C Reinardy

    Full Text Available Echinoderms represent a phylum with exceptional regenerative capabilities that can reconstruct both external appendages and internal organs. Mechanistic understanding of the cellular pathways involved in regeneration in these animals has been hampered by the limited genomic tools and limited ability to manipulate regenerative processes. We present a functional assay to investigate mechanisms of tissue regeneration and biomineralization by measuring the regrowth of amputated tube feet (sensory and motor appendages and spines in the sea urchin, Lytechinus variegatus. The ability to manipulate regeneration was demonstrated by concentration-dependent inhibition of regrowth of spines and tube feet by treatment with the mitotic inhibitor, vincristine. Treatment with the gamma-secretase inhibitor DAPT resulted in a concentration-dependent inhibition of regrowth, indicating that both tube feet and spine regeneration require functional Notch signaling. Stem cell markers (Piwi and Vasa were expressed in tube feet and spine tissue, and Vasa-positive cells were localized throughout the epidermis of tube feet by immunohistochemistry, suggesting the existence of multipotent progenitor cells in these highly regenerative appendages. The presence of Vasa protein in other somatic tissues (e.g. esophagus, radial nerve, and a sub-population of coelomocytes suggests that multipotent cells are present throughout adult sea urchins and may contribute to normal homeostasis in addition to regeneration. Mechanistic insight into the cellular pathways governing the tremendous regenerative capacity of echinoderms may reveal processes that can be modulated for regenerative therapies, shed light on the evolution of regeneration, and enable the ability to predict how these processes will respond to changing environmental conditions.

  4. Somatic embryogenesis and plant regeneration from cell suspension cultures of Cucumis sativus L.

    Chee, P P; Tricoli, D M

    1988-06-01

    A procedure for the regeneration of whole cucumber plants (Cucumis sativus L. cv. Poinsett 76) by embryogenesis from cell suspension cultures is described. Embryogenic callus was initiated from the primary leaves of 14-17 day old plants. Suspension cultures of embryogenic cells were grown in liquid Murashige and Skoog basal medium containing 5 uM 2,4,5-trichlorophenoxyacetic acid and 4 uM 6-benzylaminopurine. Suspension cultures were composed of a population of cells that were densely cytoplasmic and potentially embryogenic. Differentiation of embryos was enhanced by washing the suspension culture cells with MS basal medium containing 0.5% activated charcoal and twice with MS basal medium followed by liquid shake cultures in MS basal medium. Sixty to 70 percent of the embryos prewashed with activated charcoal germinated into plantlets with normal morphology. Embryos obtained from suspension cultured cells without prewashing with activated charcoal organized into plantlets with abnormal primary leaves. Morphologically normal plantlets were obtained by excising the shoot tips and transferring them to fresh medium.

  5. Biofunctionalized Lysophosphatidic Acid/Silk Fibroin Film for Cornea Endothelial Cell Regeneration

    Jeon, Hayan; Oliveira, Joaquim Miguel; Reis, Rui Luis; Khang, Gilson

    2018-01-01

    Cornea endothelial cells (CEnCs) tissue engineering is a great challenge to repair diseased or damaged CEnCs and require an appropriate biomaterial to support cell proliferation and differentiation. Biomaterials for CEnCs tissue engineering require biocompatibility, tunable biodegradability, transparency, and suitable mechanical properties. Silk fibroin-based film (SF) is known to meet these factors, but construction of functionalized graft for bioengineering of cornea is still a challenge. Herein, lysophosphatidic acid (LPA) is used to maintain and increase the specific function of CEnCs. The LPA and SF composite film (LPA/SF) was fabricated in this study. Mechanical properties and in vitro studies were performed using a rabbit model to demonstrate the characters of LPA/SF. ATR-FTIR was characterized to identify chemical composition of the films. The morphological and physical properties were performed by SEM, AFM, transparency, and contact angle. Initial cell density and MTT were performed for adhesion and cell viability in the SF and LPA/SF film. Reverse transcription polymerase chain reactions (RT-PCR) and immunofluorescence were performed to examine gene and protein expression. The results showed that films were designed appropriately for CEnCs delivery. Compared to pristine SF, LPA/SF showed higher biocompatibility, cell viability, and expression of CEnCs specific genes and proteins. These indicate that LPA/SF, a new biomaterial, offers potential benefits for CEnCs tissue engineering for regeneration. PMID:29710848

  6. Establishment of Cell Suspension Culture and Plant Regeneration in Abrus precatorius L., a Rare Medicinal Plant

    Mohammad Serajur RAHMAN

    2012-02-01

    Full Text Available A new protocol has been developed for cell culture and in vitro regeneration of Abrus precatorius that holds enormous potentiality for preparation of medicines. In vitro grown calli were cultured in Murashige and Skoog (MS liquid media in agitated condition fortified with 0.5 mg/l 6-Benzylaminopurine. Growth curve of cells revealed that the cells continued to grow until 12 days of culture and got the highest peak from day 6-8. Isolated cell was found to produce highest 8.2% calli when suspended on MS medium supplemented with 0.5 mg/l 6-Benzylaminopurine and 0.1 mg/l 1-Naphthaleneacetic acid. Callus derived from single cell produced highest number of embryo (25-28% cultured on MS medium fortified with 2.0 mg/l 6-Benzylaminopurine and 0.2 mg/l 1-Naphthaleneacetic acid. The bipolar embryos were selected and optimum shoot formation was recorded on MS medium supplemented with 2.0 mg/l 6-Benzylaminopurine and 0.1 mg/l 1-Naphthaleneacetic acid. The optimum root induction was noticed in MS medium supplemented with 1.0 mg/l 3-Indolebutyric acid. Rooted plantlets were successfully transferred to potting soil and acclimatized to outdoor conditions.

  7. Protein-releasing polymeric scaffolds induce fibrochondrocytic differentiation of endogenous cells for knee meniscus regeneration in sheep

    Lee, Chang H.; Rodeo, Scott A.; Fortier, Lisa Ann; Lu, Chuanyong; Erisken, Cevat

    2015-01-01

    Regeneration of complex tissues, such as kidney, liver, and cartilage, continues to be a scientific and translational challenge. Survival of ex vivo cultured, transplanted cells in tissue grafts is among one of the key barriers. Meniscus is a complex tissue consisting of collagen fibers and proteoglycans with gradient phenotypes of fibrocartilage and functions to provide congruence of the knee joint, without which the patient is likely to develop arthritis. Endogenous stem/progenitor cells regenerated the knee meniscus upon spatially released human connective tissue growth factor (CTGF) and trans