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Pourjabbar B, Shams F, Heidari Keshel S, Biazar E. Proliferation and differentiation of Wharton's jelly-derived mesenchymal stem cells on prgf-treated hydrogel scaffold. Regen Med 2024; 19:549-560. [PMID: 39558722 PMCID: PMC11633401 DOI: 10.1080/17460751.2024.2427513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 11/04/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND To address the limitations of Cultivated Limbal Epithelial Transplantation (CLET) and the use of amniotic membrane (AM) in treating Limbal Stem Cell Deficiency (LSCD), we aimed to develop a Collagen/Silk Fibroin (Co/SF) scaffold enriched with Platelet-Rich Growth Factor (PRGF) to support the proliferation, maintenance, and differentiation of Wharton's jelly-derived mesenchymal stem cells (WJMSCs) into corneal epithelial cells (CECs). METHOD Scaffolds loaded with PRGF were evaluated through release studies, cytotoxicity assays, and cell differentiation. The proliferation and differentiation of WJMSCs and Limbal Epithelial Stem Cells (LESCs) were investigated using MTT assays, real-time PCR and immunostaining. RESULTS The PRGF-loaded Co/SF scaffold significantly promoted the proliferation of both WJMSCs and LESCs in a concentration-dependent manner. Real-time PCR and immune staining revealed a significant increase in the expression of P63, ABCG2, and cytokeratin 3/12 markers in WJMSCs, a significant decrease in the expression of P63 and ABCG2, and a significant increase in the expression of cytokeratin 3/12 markers indicating successful differentiation into CECs. CONCLUSION The WJMSC cultured on PRGF-enriched Co/SF scaffold demonstrates potential as a viable alternative to conventional CLET, offering a promising strategy for corneal tissue regeneration.
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Affiliation(s)
- Bahareh Pourjabbar
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Forough Shams
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Medical Nanotechnology and Tissue Engineering Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Esmaeil Biazar
- Tissue Engineering Group, Department of Biomedical Engineering, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
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Li S, Rong Q, Zhou Y, Che Y, Ye Z, Liu J, Wang J, Zhou M. Osteogenically committed hUCMSCs-derived exosomes promote the recovery of critical-sized bone defects with enhanced osteogenic properties. APL Bioeng 2024; 8:016107. [PMID: 38327715 PMCID: PMC10849773 DOI: 10.1063/5.0159740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 12/18/2023] [Indexed: 02/09/2024] Open
Abstract
Low viability of seed cells and the concern about biosafety restrict the application of cell-based tissue-engineered bone (TEB). Exosomes that bear similar bioactivities to donor cells display strong stability and low immunogenicity. Human umbilical cord mesenchymal stem cells-derived exosomes (hUCMSCs-Exos) show therapeutic efficacy in various diseases. However, little is known whether hUCMSCs-Exos can be used to construct TEB to repair bone defects. Herein, PM-Exos and OM-Exos were separately harvested from hUCMSCs which were cultured in proliferation medium (PM) or osteogenic induction medium (OM). A series of in-vitro studies were performed to evaluate the bioactivities of human bone marrow mesenchymal stem cells (hBMSCs) when co-cultured with PM-Exos or OM-Exos. Differential microRNAs (miRNAs) between PM-Exos and OM-Exos were sequenced and analyzed. Furthermore, PM-Exos and OM-Exos were incorporated in 3D printed tricalcium phosphate scaffolds to build TEBs for the repair of critical-sized calvarial bone defects in rats. Results showed that PM-Exos and OM-Exos bore similar morphology and size. They expressed representative surface markers of exosomes and could be internalized by hBMSCs to promote cellular migration and proliferation. OM-Exos outweighed PM-Exos in accelerating the osteogenic differentiation of hBMSCs, which might be attributed to the differentially expressed miRNAs. Furthermore, OM-Exos sustainably released from the scaffolds, and the resultant TEB showed a better reparative outcome than that of the PM-Exos group. Our study found that exosomes isolated from osteogenically committed hUCMSCs prominently facilitated the osteogenic differentiation of hBMSCs. TEB grafts functionalized by OM-Exos bear a promising application potential for the repair of large bone defects.
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Affiliation(s)
| | | | | | - Yuejuan Che
- Department of Anesthesia, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Ziming Ye
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou 510182, China
| | - Junfang Liu
- Department of Oral and Maxillofacial Surgery, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou 510182, China
| | - Jinheng Wang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou 511436, China
| | - Miao Zhou
- Author to whom correspondence should be addressed:. Tel/Fax: +86 020 33976070
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Kao YH, Chang CY, Lin YC, Chen PH, Lee PH, Chang HR, Chang WY, Chang YC, Wun SF, Sun CK. Mesenchymal Stem Cell-Derived Exosomes Mitigate Acute Murine Liver Injury via Ets-1 and Heme Oxygenase-1 Up-regulation. Curr Stem Cell Res Ther 2024; 19:906-918. [PMID: 37723631 DOI: 10.2174/1574888x19666230918102826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/21/2023] [Accepted: 08/11/2023] [Indexed: 09/20/2023]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs)-derived exosomes have been previously demonstrated to promote tissue regeneration in various animal disease models. This study investigated the protective effect of exosome treatment in carbon tetrachloride (CCl4)-induced acute liver injury and delineated possible underlying mechanism. METHODS Exosomes collected from conditioned media of previously characterized human umbilical cord-derived MSCs were intravenously administered into male CD-1 mice with CCl4-induced acute liver injury. Biochemical, histological and molecular parameters were used to evaluate the severity of liver injury. A rat hepatocyte cell line, Clone-9, was used to validate the molecular changes by exosome treatment. RESULTS Exosome treatment significantly suppressed plasma levels of AST, ALT, and pro-inflammatory cytokines, including IL-6 and TNF-α, in the mice with CCl4-induced acute liver injury. Histological morphometry revealed a significant reduction in the necropoptic area in the injured livers following exosome therapy. Consistently, western blot analysis indicated marked elevations in hepatic expression of PCNA, c-Met, Ets-1, and HO-1 proteins after exosome treatment. Besides, the phosphorylation level of signaling mediator JNK was significantly increased, and that of p38 was restored by exosome therapy. Immunohistochemistry double staining confirmed nuclear Ets-1 expression and cytoplasmic localization of c-Met and HO-1 proteins. In vitro studies demonstrated that exosome treatment increased the proliferation of Clone-9 hepatocytes and protected them from CCl4-induced cytotoxicity. Kinase inhibition experiment indicated that the exosome-driven hepatoprotection might be mediated through the JNK pathway. CONCLUSION Exosome therapy activates the JNK signaling activation pathway as well as up-regulates Ets-1 and HO-1 expression, thereby protecting hepatocytes against hepatotoxin-induced cell death.
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Affiliation(s)
- Ying-Hsien Kao
- Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, 82445, Taiwan
| | - Chih-Yang Chang
- Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, E-Da Hospital, I-Shou University, Kaohsiung, 82445, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, 82445, Taiwan
| | - Yu-Chun Lin
- Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, 52445, Taiwan
| | - Po-Han Chen
- Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, 82445, Taiwan
| | - Po-Huang Lee
- Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, 52445, Taiwan
- Committee for Integration and Promotion of Advanced Medicine and Biotechnology, E-Da Healthcare Group, Kaohsiung, 82445, Taiwan
| | - Huoy-Rou Chang
- Departments of Biomedical Engineering, I-Shou University, Kaohsiung, 82445, Taiwan
| | - Wen-Yu Chang
- Department of Dermatology, EDa Cancer Hospital, I-Shou University, Kaohsiung, 82445, Taiwan
- The School of Medicine for International Students, College of Medicine, IShou University, Kaohsiung, 82445, Taiwan
| | - Yo-Chen Chang
- Department of Ophthalmology, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Shen-Fa Wun
- Departments of Biomedical Engineering, I-Shou University, Kaohsiung, 82445, Taiwan
| | - Cheuk-Kwan Sun
- Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung, 82445, Taiwan
- The School of Medicine for International Students, College of Medicine, IShou University, Kaohsiung, 82445, Taiwan
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Baouche M, Krawczenko A, Paprocka M, Klimczak A, Mermillod P, Locatelli Y, Ochota M, Niżański W. Feline umbilical cord mesenchymal stem cells: Isolation and in vitro characterization from distinct parts of the umbilical cord. Theriogenology 2023; 201:116-125. [PMID: 36889011 DOI: 10.1016/j.theriogenology.2022.11.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/30/2022] [Accepted: 11/30/2022] [Indexed: 12/05/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) are a particular population of cells that play an essential role in the regeneration potential of the body. As a source of MSCs, the umbilical cord (UC) has significant advantages, such as a no-risk procedure of tissue retrieval after birth and the easiness of MSCs isolation. In the presented study, the cells derived from the feline whole umbilical cord (WUC) and two separate parts of the UC tissue, including Wharton's jelly (WJ) and umbilical cord vessels (UCV), were investigated to check whether they exhibit MSCs characteristics. The cells were isolated and characterized based on their morphology, pluripotency, differentiation potential, and phenotype. In our study MSCs were successfully isolated and cultured from all UC parts; after one week of culture, the cells had a typical spindle shape consistent with MSCs morphology. Cells showed the ability to differentiate into chondrocytes, osteoblasts and adipocytes cells. Two markers typical of MSCs (CD44, CD90) and three pluripotency markers (Oct4, SOX2 and Nanog) were expressed in all cells cultures; but no expression of (CD34, MCH II) was evidenced by flow cytometry and RT-PCR. In addition, WJ-MSCs showed the highest ability of proliferation, more significant pluripotency gene expressions, and greater differentiation potential than the cells isolated from WUC and UCV. Finally, we conclude in this study that cat MSCs derived from all the parts are valuable cells that can be efficiently used in various fields of feline regenerative medicine, but cells from WJ can offer the best clinical utility.
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Affiliation(s)
- Meriem Baouche
- Wrocław University of Environmental and Life Sciences, Department of Reproduction and Clinic of Farm Animals, 50-366, Wrocław, Poland
| | - Agnieszka Krawczenko
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114, Wroclaw, Poland
| | - Maria Paprocka
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114, Wroclaw, Poland
| | - Aleksandra Klimczak
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, R. Weigla 12, 53-114, Wroclaw, Poland
| | - Pascal Mermillod
- Physiology of Reproduction and Behaviors (PR China), UMR085, INRAE, CNRS, University of Tours, 37380, Nouzilly, France
| | - Yann Locatelli
- Physiology of Reproduction and Behaviors (PR China), UMR085, INRAE, CNRS, University of Tours, 37380, Nouzilly, France; Museum National d'Histoire Naturelle, Réserve Zoologique de la Haute Touche, 36290, Obterre, France
| | - Małgorzata Ochota
- Wrocław University of Environmental and Life Sciences, Department of Reproduction and Clinic of Farm Animals, 50-366, Wrocław, Poland.
| | - Wojciech Niżański
- Wrocław University of Environmental and Life Sciences, Department of Reproduction and Clinic of Farm Animals, 50-366, Wrocław, Poland.
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Deo D, Marchioni M, Rao P. Mesenchymal Stem/Stromal Cells in Organ Transplantation. Pharmaceutics 2022; 14:pharmaceutics14040791. [PMID: 35456625 PMCID: PMC9029865 DOI: 10.3390/pharmaceutics14040791] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 02/07/2023] Open
Abstract
Organ transplantation is essential and crucial for saving and enhancing the lives of individuals suffering from end-stage organ failure. Major challenges in the medical field include the shortage of organ donors, high rates of organ rejection, and long wait times. To address the current limitations and shortcomings, cellular therapy approaches have been developed using mesenchymal stem/stromal cells (MSC). MSC have been isolated from various sources, have the ability to differentiate to important cell lineages, have anti-inflammatory and immunomodulatory properties, allow immunosuppressive drug minimization, and induce immune tolerance towards the transplanted organ. Additionally, rapid advances in the fields of tissue engineering and regenerative medicine have emerged that focus on either generating new organs and organ sources or maximizing the availability of existing organs. This review gives an overview of the various properties of MSC that have enabled its use as a cellular therapy for organ preservation and transplant. We also highlight emerging fields of tissue engineering and regenerative medicine along with their multiple sub-disciplines, underlining recent advances, widespread clinical applications, and potential impact on the future of tissue and organ transplantation.
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Rahmani-Moghadam E, Zarrin V, Mahmoodzadeh A, Owrang M, Talaei-Khozani T. Comparison of the Characteristics of Breast Milk-derived Stem Cells with the Stem Cells Derived from the Other Sources: A Comparative Review. Curr Stem Cell Res Ther 2021; 17:71-90. [PMID: 34161214 DOI: 10.2174/1574888x16666210622125309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/14/2021] [Accepted: 03/28/2021] [Indexed: 11/22/2022]
Abstract
Breast milk (BrM) not only supplies nutrition, but it also contains a diverse population of cells. It has been estimated that up to 6% of the cells in human milk possess the characteristics of mesenchymal stem cells (MSC). Available data also indicate that these cells are multipotent and capable of self-renewal and differentiation with other cells. In this review, we have compared different characteristics, such as CD markers, differentiation capacity, and morphology of stem cells, derived from human breast milk (hBr-MSC) with human bone marrow (hBMSC), Wharton's jelly (WJMSC), and human adipose tissue (hADMSC). Through the literature review, it was revealed that human breast milk-derived stem cells specifically express a group of cell surface markers, including CD14, CD31, CD45, and CD86. Importantly, a group of markers, CD13, CD29, CD44, CD105, CD106, CD146, and CD166, were identified, which were common in the four sources of stem cells. WJMSC, hBMSC, hADMSC, and hBr-MSC are potently able to differentiate into the mesoderm, ectoderm, and endoderm cell lineages. The ability of hBr-MSCs todifferentiate into the neural stem cells, neurons, adipocyte, hepatocyte, chondrocyte, osteocyte, and cardiomyocytes has made these cells a promising source of stem cells in regenerative medicine, while isolation of stem cells from the commonly used sources, such as bone marrow, requires invasive procedures. Although autologous breast milk-derived stem cells are an accessible source for women who are in the lactation period, breast milk can be considered as a source of stem cells with high differentiation potential without any ethical concern.
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Affiliation(s)
- Ebrahim Rahmani-Moghadam
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahideh Zarrin
- Laboratory for Stem Cell Research, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Mahmoodzadeh
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Marzieh Owrang
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Anatomical sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
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Human Umbilical Cord-Derived Mesenchymal Stem Cells Promote Corneal Epithelial Repair In Vitro. Cells 2021; 10:cells10051254. [PMID: 34069578 PMCID: PMC8160941 DOI: 10.3390/cells10051254] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/08/2021] [Accepted: 05/14/2021] [Indexed: 12/31/2022] Open
Abstract
Corneal injuries are among the leading causes of blindness and vision impairment. Trauma, infectious keratitis, thermal and chemical (acids and alkali burn) injuries may lead to irreversible corneal scarring, neovascularization, conjunctivalization, and limbal stem cell deficiency. Bilateral blindness constitutes 12% of total global blindness and corneal transplantation remains a stand-alone treatment modality for the majority of end-stage corneal diseases. However, global shortage of donor corneas, the potential risk of graft rejection, and severe side effects arising from long-term use of immunosuppressive medications, demands alternative therapeutic approaches. Umbilical cord-derived mesenchymal stem cells can be isolated in large numbers using a relatively less invasive procedure. However, their role in injury induced corneal repair is largely unexplored. Here, we isolated, cultured and characterized mesenchymal stem cells from human umbilical cord, and studied the expression of mesenchymal (CD73, CD90, CD105, and CD34), ocular surface and epithelial (PAX6, WNT7A, and CK-8/18) lineage markers through immunofluorescence. The cultured human limbal and corneal epithelial cells were used as controls. Scratch assay was used to study the corneal epithelial repair potential of umbilical cord-derived mesenchymal stem cells, in vitro. The in vitro cultured umbilical cord-derived mesenchymal stem cells were plastic adherent, showed trilineage differentiation and expressed: mesenchymal markers CD90, CD105, CD73; epithelial marker CK-8/18, and ocular lineage developmental markers PAX6 and WNT-7A. Our findings suggest that umbilical cord-derived mesenchymal stem cells promote repair of the injured corneal epithelium by stimulating the proliferation of corneal epithelial cells, in vitro. They may serve as a potential non-ocular source of stem cells for treating injury induced bilateral corneal diseases.
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Altundag Ö, Çelebi-Saltik B. From Embryo to Adult: One Carbon Metabolism in Stem Cells. Curr Stem Cell Res Ther 2021; 16:175-188. [PMID: 32652922 DOI: 10.2174/1574888x15666200712191308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 04/16/2020] [Accepted: 04/23/2020] [Indexed: 11/22/2022]
Abstract
Stem cells are undifferentiated cells with self-renewal property and varying differentiation potential that allow the regeneration of tissue cells of an organism throughout adult life beginning from embryonic development. Through the asymmetric cell divisions, each stem cell replicates itself and produces an offspring identical with the mother cell, and a daughter cell that possesses the characteristics of a progenitor cell and commits to a specific lineage to differentiate into tissue cells to maintain homeostasis. To maintain a pool of stem cells to ensure tissue regeneration and homeostasis, it is important to regulate the metabolic functioning of stem cells, progenitor cells and adult tissue stem cells that will meet their internal and external needs. Upon fertilization, the zygote transforms metabolic reprogramming while implantation, embryonic development, organogenesis processes and after birth through adult life. Metabolism in stem cells is a concept that is relatively new to be enlightened. There are no adequate and comprehensive in vitro studies on the comparative analysis of the effects of one-carbon (1-C) metabolism on fetal and adult stem cells compared to embryonic and cancer stem cells' studies that have been reported recently. Since 1-C metabolism is linking parental environmental/ dietary factors and fetal development, investigating the epigenetic, genetic, metabolic and developmental effects on adult period is necessary. Several mutations and abnormalities in 1-C metabolism have been noted in disease changing from diabetes, cancer, pregnancy-related outcomes such as pre-eclampsia, spontaneous abortion, placental abruption, premature delivery, and cardiovascular diseases. In this review, the effects of 1-C metabolism, mainly the methionine and folate metabolism, in stem cells that exist in different developmental stages will be discussed.
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Affiliation(s)
- Özlem Altundag
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, 06100, Sihhiye, Ankara, Turkey
| | - Betül Çelebi-Saltik
- Department of Stem Cell Sciences, Hacettepe University Graduate School of Health Sciences, 06100, Sihhiye, Ankara, Turkey
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de la Torre P, Flores AI. Current Status and Future Prospects of Perinatal Stem Cells. Genes (Basel) 2020; 12:6. [PMID: 33374593 PMCID: PMC7822425 DOI: 10.3390/genes12010006] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/18/2020] [Accepted: 12/20/2020] [Indexed: 02/05/2023] Open
Abstract
The placenta is a temporary organ that is discarded after birth and is one of the most promising sources of various cells and tissues for use in regenerative medicine and tissue engineering, both in experimental and clinical settings. The placenta has unique, intrinsic features because it plays many roles during gestation: it is formed by cells from two individuals (mother and fetus), contributes to the development and growth of an allogeneic fetus, and has two independent and interacting circulatory systems. Different stem and progenitor cell types can be isolated from the different perinatal tissues making them particularly interesting candidates for use in cell therapy and regenerative medicine. The primary source of perinatal stem cells is cord blood. Cord blood has been a well-known source of hematopoietic stem/progenitor cells since 1974. Biobanked cord blood has been used to treat different hematological and immunological disorders for over 30 years. Other perinatal tissues that are routinely discarded as medical waste contain non-hematopoietic cells with potential therapeutic value. Indeed, in advanced perinatal cell therapy trials, mesenchymal stromal cells are the most commonly used. Here, we review one by one the different perinatal tissues and the different perinatal stem cells isolated with their phenotypical characteristics and the preclinical uses of these cells in numerous pathologies. An overview of clinical applications of perinatal derived cells is also described with special emphasis on the clinical trials being carried out to treat COVID19 pneumonia. Furthermore, we describe the use of new technologies in the field of perinatal stem cells and the future directions and challenges of this fascinating and rapidly progressing field of perinatal cells and regenerative medicine.
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Affiliation(s)
| | - Ana I. Flores
- Grupo de Medicina Regenerativa, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Avda. Cordoba s/n, 28041 Madrid, Spain;
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Ciardulli MC, Marino L, Lamparelli EP, Guida M, Forsyth NR, Selleri C, Della Porta G, Maffulli N. Dose-Response Tendon-Specific Markers Induction by Growth Differentiation Factor-5 in Human Bone Marrow and Umbilical Cord Mesenchymal Stem Cells. Int J Mol Sci 2020; 21:E5905. [PMID: 32824547 PMCID: PMC7460605 DOI: 10.3390/ijms21165905] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/10/2020] [Accepted: 08/14/2020] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells derived from human bone marrow (hBM-MSCs) are utilized in tendon tissue-engineering protocols while extra-embryonic cord-derived, including from Wharton's Jelly (hWJ-MSCs), are emerging as useful alternatives. To explore the tenogenic responsiveness of hBM-MSCs and hWJ-MSCs to human Growth Differentiation Factor 5 (hGDF-5) we supplemented each at doses of 1, 10, and 100 ng/mL of hGDF-5 and determined proliferation, morphology and time-dependent expression of tenogenic markers. We evaluated the expression of collagen types 1 (COL1A1) and 3 (COL3A1), Decorin (DCN), Scleraxis-A (SCX-A), Tenascin-C (TNC) and Tenomodulin (TNMD) noting the earliest and largest increase with 100 ng/mL. With 100 ng/mL, hBM-MSCs showed up-regulation of SCX-A (1.7-fold) at Day 1, TNC (1.3-fold) and TNMD (12-fold) at Day 8. hWJ-MSCs, at the same dose, showed up-regulation of COL1A1 (3-fold), DCN (2.7-fold), SCX-A (3.8-fold) and TNC (2.3-fold) after three days of culture. hWJ-MSCs also showed larger proliferation rate and marked aggregation into a tubular-shaped system at Day 7 (with 100 ng/mL of hGDF-5). Simultaneous to this, we explored the expression of pro-inflammatory (IL-6, TNF, IL-12A, IL-1β) and anti-inflammatory (IL-10, TGF-β1) cytokines across for both cell types. hBM-MSCs exhibited a better balance of pro-inflammatory and anti-inflammatory cytokines up-regulating IL-1β (11-fold) and IL-10 (10-fold) at Day 8; hWJ-MSCs, had a slight expression of IL-12A (1.5-fold), but a greater up-regulation of IL-10 (2.5-fold). Type 1 collagen and tenomodulin proteins, detected by immunofluorescence, confirming the greater protein expression when 100 ng/mL were supplemented. In the same conditions, both cell types showed specific alignment and shape modification with a length/width ratio increase, suggesting their response in activating tenogenic commitment events, and they both potential use in 3D in vitro tissue-engineering protocols.
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Affiliation(s)
- Maria Camilla Ciardulli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via S. Allende, 1, 84084 Baronissi (SA), Italy; (M.C.C.); (L.M.); (E.P.L.); (C.S.); (N.M.)
| | - Luigi Marino
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via S. Allende, 1, 84084 Baronissi (SA), Italy; (M.C.C.); (L.M.); (E.P.L.); (C.S.); (N.M.)
| | - Erwin Pavel Lamparelli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via S. Allende, 1, 84084 Baronissi (SA), Italy; (M.C.C.); (L.M.); (E.P.L.); (C.S.); (N.M.)
| | - Maurizio Guida
- Department of Neuroscience and Reproductive Science and Dentistry, University of Naples “Federico II”, Via Pansini, 5, 80131 Naples, Italy;
| | - Nicholas Robert Forsyth
- Guy Hilton Research Centre, School of Pharmacy and Bioengineering, Keele University, Stoke-on-Trent ST4 7QB, UK;
| | - Carmine Selleri
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via S. Allende, 1, 84084 Baronissi (SA), Italy; (M.C.C.); (L.M.); (E.P.L.); (C.S.); (N.M.)
| | - Giovanna Della Porta
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via S. Allende, 1, 84084 Baronissi (SA), Italy; (M.C.C.); (L.M.); (E.P.L.); (C.S.); (N.M.)
| | - Nicola Maffulli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via S. Allende, 1, 84084 Baronissi (SA), Italy; (M.C.C.); (L.M.); (E.P.L.); (C.S.); (N.M.)
- Mile End Hospital, Centre for Sports and Exercise Medicine, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, 275 Bancroft Road, London E1 4DG, UK
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Sriramulu S, Banerjee A, Jothimani G, Pathak S. Conditioned medium from the human umbilical cord-mesenchymal stem cells stimulate the proliferation of human keratinocytes. J Basic Clin Physiol Pharmacol 2020; 32:51-56. [PMID: 32549126 DOI: 10.1515/jbcpp-2019-0283] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 02/08/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVES Wound healing is a complex process with a sequence of restoring and inhibition events such as cell proliferation, differentiation, migration as well as adhesion. Mesenchymal stem cells (MSC) derived conditioned medium (CM) has potent therapeutic functions and promotes cell proliferation, anti-oxidant, immunosuppressive, and anti-apoptotic effects. The main aim of this research is to study the role of human umbilical cord-mesenchymal stem cells (UC-MSCs) derived CM in stimulating the proliferation of human keratinocytes (HaCaT). METHODS Firstly, MSC were isolated from human umbilical cords (UC) and the cells were then cultured in proliferative medium. We prepared and collected the CM after 72 h. Morphological changes were observed after the treatment of HaCaT cells with CM. To validate the findings, proliferation rate, clonal efficiency and also gene expression studies were performed. RESULTS Increased proliferation rate was observed and confirmed with the expression of Proliferating Cell Nuclear Antigen (PCNA) after treatment with HaCaT cells. Cell-cell strap formation was also observed when HaCaT cells were treated with CM for a period of 5-6 days which was confirmed by the increased expression of Collagen Type 1 Alpha 1 chain (Col1A1). CONCLUSIONS Our results from present study depicts that the secretory components in the CM might play a significant role by interacting with keratinocytes to promote proliferation and migration. Thus, the CM stimulates cellular proliferation, epithelialization and migration of skin cells which might be the future promising application in wound healing.
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Affiliation(s)
- Sushmitha Sriramulu
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603103, TN, India
| | - Antara Banerjee
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603103, TN, India
| | - Ganesan Jothimani
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603103, TN, India
| | - Surajit Pathak
- Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Kelambakkam, Chennai, 603103, TN, India
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Shen J, Cao D, Sun JL. Ability of human umbilical cord mesenchymal stem cells to repair chemotherapy-induced premature ovarian failure. World J Stem Cells 2020; 12:277-287. [PMID: 32399136 PMCID: PMC7202924 DOI: 10.4252/wjsc.v12.i4.277] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 03/23/2020] [Accepted: 03/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Premature ovarian insufficiency (POI) and premature ovarian failure (POF) have become one of the major problems threatening women of childbearing age. Studies have shown that stem cells transplanted from bone marrow, umbilical cord, peripheral blood and amniotic fluid can migrate and proliferate to the ovary, promote ovarian function repair, increase the number of follicles and granulosa cells at all levels of ovary, improve endocrine function, and can differentiate into oocytes in specific ovarian environment to restore fertility to some extent.
AIM To study the ability of human umbilical cord mesenchymal stem cells (hUCMSCs) to repair ovarian injury after chemotherapy.
METHODS A total of 110 female BALB/c mice (aged 7-8 wk old) with body masses of 16.0-20.0 g were selected. The mice were fed until 12 wk of age, and cyclophosphamide was administered by intraperitoneal injection for 14 consecutive days to induce premature ovarian failure in mice. Seventy-five mice with estrous cycle disorder were screened and randomly divided into 3 groups according to their body weight: model group, positive control group and hUCMSC group, and each group had 25 mice. Another 25 mice were used as negative controls. The mice in the hUCMSC group were injected with hUCMSCs in the tail vein, and the mice in the positive control group were given an oestradiol valerate solution and a medroxyprogesterone acetate solution in the tail vein. On the 1st, 15th, 30th, 45th, and 60th days after intravenous administration, vaginal smears were made to monitor the estrous cycles of the mice. The ovaries were weighed, and pathological sections were made to observe the morphology of the follicles; blood samples were collected to monitor the concentration of sex hormones (oestradiol and follicle-stimulating hormone).
RESULTS The estrous cycles of the model group mice were disrupted throughout the experiment. Mice in the hUCMSC group and the positive control group resumed normal estrous cycles. The ovarian weight of the model group mice continued to decline. The ovarian weight of the hUCMSC group mice and the positive control group mice decreased first and then gradually increased, and the ovarian weight of the hUCMSC group mice was heavier than that of the positive control group mice. The difference was statistically significant (P < 0.05). Compared with the negative control group, the model group experienced a decrease in oestradiol and an increase in follicle-stimulating hormone, and the difference was statistically significant (P < 0.05). Compared with the model group, the hUCMSC and positive control groups experienced a slight increase in oestradiol and a decrease in follicle-stimulating hormone; the difference was statistically significant (P < 0.05). The pathological examination revealed that the mouse ovaries from the model group were atrophied, the volume was reduced, the cortical and medullary structures were disordered, the number of follicles at all stages was significantly reduced, the number of atretic follicles increased, the number of primordial follicles and corpus luteum significantly decreased, and the corpus luteum had an irregular shape. Compared with those of the model group, the lesions of the hUCMSC and positive control groups significantly improved.
CONCLUSION hUCMSCs can repair ovarian tissue damaged by chemotherapy to a certain extent, can improve the degree of apoptosis in ovarian tissue, and can improve the endocrine function of mouse ovaries.
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Affiliation(s)
- Jian Shen
- Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command (Heping Campus), Shenyang 110000, Liaoning Province, China
| | - Dai Cao
- Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command (Heping Campus), Shenyang 110000, Liaoning Province, China
| | - Jing-Li Sun
- Department of Obstetrics and Gynecology, General Hospital of Northern Theater Command (Heping Campus), Shenyang 110000, Liaoning Province, China
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Human Wharton's Jelly-Cellular Specificity, Stemness Potency, Animal Models, and Current Application in Human Clinical Trials. J Clin Med 2020; 9:jcm9041102. [PMID: 32290584 PMCID: PMC7230974 DOI: 10.3390/jcm9041102] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/30/2020] [Accepted: 04/10/2020] [Indexed: 12/14/2022] Open
Abstract
Stem cell therapies offer a great promise for regenerative and reconstructive medicine, due to their self-renewal and differentiation capacity. Although embryonic stem cells are pluripotent, their utilization involves embryo destruction and is ethically controversial. Therefore, adult tissues that have emerged as an alternative source of stem cells and perinatal tissues, such as the umbilical cord, appear to be particularly attractive. Wharton's jelly, a gelatinous connective tissue contained in the umbilical cord, is abundant in mesenchymal stem cells (MSCs) that express CD105, CD73, CD90, Oct-4, Sox-2, and Nanog among others, and have the ability to differentiate into osteogenic, adipogenic, chondrogenic, and other lineages. Moreover, Wharton's jelly-derived MSCs (WJ-MSCs) do not express MHC-II and exhibit immunomodulatory properties, which makes them a good alternative for allogeneic and xenogeneic transplantations in cellular therapies. Therefore, umbilical cord, especially Wharton's jelly, is a promising source of mesenchymal stem cells.
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Tey SR, Robertson S, Lynch E, Suzuki M. Coding Cell Identity of Human Skeletal Muscle Progenitor Cells Using Cell Surface Markers: Current Status and Remaining Challenges for Characterization and Isolation. Front Cell Dev Biol 2019; 7:284. [PMID: 31828070 PMCID: PMC6890603 DOI: 10.3389/fcell.2019.00284] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 11/01/2019] [Indexed: 12/12/2022] Open
Abstract
Skeletal muscle progenitor cells (SMPCs), also called myogenic progenitors, have been studied extensively in recent years because of their promising therapeutic potential to preserve and recover skeletal muscle mass and function in patients with cachexia, sarcopenia, and neuromuscular diseases. SMPCs can be utilized to investigate the mechanisms of natural and pathological myogenesis via in vitro modeling and in vivo experimentation. While various types of SMPCs are currently available from several sources, human pluripotent stem cells (PSCs) offer an efficient and cost-effective method to derive SMPCs. As human PSC-derived cells often display varying heterogeneity in cell types, cell enrichment using cell surface markers remains a critical step in current procedures to establish a pure population of SMPCs. Here we summarize the cell surface markers currently being used to detect human SMPCs, describing their potential application for characterizing, identifying and isolating human PSC-derived SMPCs. To date, several positive and negative markers have been used to enrich human SMPCs from differentiated PSCs by cell sorting. A careful analysis of current findings can broaden our understanding and reveal potential uses for these surface markers with SMPCs.
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Affiliation(s)
- Sin-Ruow Tey
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States
| | - Samantha Robertson
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States
| | - Eileen Lynch
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States
| | - Masatoshi Suzuki
- Department of Comparative Biosciences, University of Wisconsin, Madison, WI, United States.,The Stem Cell and Regenerative Medicine Center, University of Wisconsin, Madison, WI, United States
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Human Umbilical Cord Mesenchymal Stem Cells Extricate Bupivacaine-Impaired Skeletal Muscle Function via Mitigating Neutrophil-Mediated Acute Inflammation and Protecting against Fibrosis. Int J Mol Sci 2019; 20:ijms20174312. [PMID: 31484417 PMCID: PMC6747081 DOI: 10.3390/ijms20174312] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 08/29/2019] [Accepted: 08/29/2019] [Indexed: 12/20/2022] Open
Abstract
Skeletal muscle injury presents a challenging traumatological dilemma, and current therapeutic options remain mediocre. This study was designed to delineate if engraftment of mesenchymal stem cells derived from umbilical cord Wharton's jelly (uMSCs) could aid in skeletal muscle healing and persuasive molecular mechanisms. We established a skeletal muscle injury model by injection of myotoxin bupivacaine (BPVC) into quadriceps muscles of C57BL/6 mice. Post BPVC injection, neutrophils, the first host defensive line, rapidly invaded injured muscle and induced acute inflammation. Engrafted uMSCs effectively abolished neutrophil infiltration and activation, and diminished neutrophil chemotaxis, including Complement component 5a (C5a), Keratinocyte chemoattractant (KC), Macrophage inflammatory protein (MIP)-2, LPS-induced CXC chemokine (LIX), Fractalkine, Leukotriene B4 (LTB4), and Interferon-γ, as determined using a Quantibody Mouse Cytokine Array assay. Subsequently, uMSCs noticeably prevented BPVC-accelerated collagen deposition and fibrosis, measured by Masson's trichrome staining. Remarkably, uMSCs attenuated BPVC-induced Transforming growth factor (TGF)-β1 expression, a master regulator of fibrosis. Engrafted uMSCs attenuated TGF-β1 transmitting through interrupting the canonical Sma- And Mad-Related Protein (Smad)2/3 dependent pathway and noncanonical Smad-independent Transforming growth factor beta-activated kinase (TAK)-1/p38 mitogen-activated protein kinases signaling. The uMSCs abrogated TGF-β1-induced fibrosis by reducing extracellular matrix components including fibronectin-1, collagen (COL) 1A1, and COL10A1. Most importantly, uMSCs modestly extricated BPVC-impaired gait functions, determined using CatWalk™ XT gait analysis. This work provides several innovative insights into and molecular bases for employing uMSCs to execute therapeutic potential through the elimination of neutrophil-mediated acute inflammation toward protecting against fibrosis, thereby rescuing functional impairments post injury.
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Wakao S, Matsuse D, Dezawa M. Mesenchymal stem cells as a source of Schwann cells: their anticipated use in peripheral nerve regeneration. Cells Tissues Organs 2015; 200:31-41. [PMID: 25765009 DOI: 10.1159/000368188] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2014] [Indexed: 11/19/2022] Open
Abstract
Schwann cells form myelin, sustain axons and provide the microenvironment for nerve fibers, thereby playing a key role in the peripheral nervous system (PNS). Schwann cells also provide support for the damaged PNS by producing factors that strongly promote axonal regrowth and contribute to remyelination, which is crucial for the recovery of neural function. These advantages are not confined to the PNS and also apply to the central nervous system. Many diseases, including peripheral nerve injury, neuropathy, multiple sclerosis and spinal cord injury, are targets for Schwann cell therapy. The collection of Schwann cells, however, causes new damage to other peripheral nerve segments. Furthermore, the doubling time of Schwann cells is not very fast, and thus adequate amounts of Schwann cells for clinical use cannot be collected within a reasonable amount of time. Mesenchymal stem cells, which are highly proliferative, are easily accessible from various types of mesenchymal tissues, such as the bone marrow, umbilical cord and fat tissue. Because these cells have the ability to cross oligolineage boundaries between mesodermal to ectodermal lineages, they are capable of differentiating into Schwann cells with step-by-step cytokine stimulation. In this review, we summarize the properties of mesenchymal stem cell-derived Schwann cells, which are comparable to authentic Schwann cells, and discuss future perspectives.
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Affiliation(s)
- Shohei Wakao
- Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Pozzobon M, Franzin C, Piccoli M, De Coppi P. Fetal stem cells and skeletal muscle regeneration: a therapeutic approach. Front Aging Neurosci 2014; 6:222. [PMID: 25221507 PMCID: PMC4145352 DOI: 10.3389/fnagi.2014.00222] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 08/05/2014] [Indexed: 12/13/2022] Open
Abstract
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 cells, namely satellite cells. Muscle diseases, in particular chronic degenerative states 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 continuous 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 no definitive cure in particular for genetic muscle disease. Keeping this in mind, in this article, we will give special consideration to muscle diseases and the use of fetal derived stem cells as a 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 immune-modulatory 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.
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Affiliation(s)
- Michela Pozzobon
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza , Padova , Italy
| | - Chiara Franzin
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza , Padova , Italy
| | - Martina Piccoli
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza , Padova , Italy
| | - Paolo De Coppi
- UCL Institute of Child Health and Great Ormond Street Hospital , London , UK
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