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      Role and effect of vein-transplanted human umbilical cord mesenchymal stem cells in the repair of diabetic foot ulcers in rats

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          Abstract

          Diabetic foot ulcer (DFU) is one of diabetic complications, which is frequently present and tormented in diabetes mellitus. Most multipotent mesenchymal stromal cells (MSCs) are capable of immune evasion, providing an allogeneic, ready-to-use, cell product option for therapeutic applications. The beneficial effect of MSCs for the treatment of a variety of traumatic injuries, such as open wounds, has been extensively explored. In this study, a rat DFU model was used to simulate the pathophysiology of clinical patients and to investigate the localization of human umbilical cord mesenchymal stem cells (hUC-MSCs) after intravenous transplantation and its role in DFU healing, so as to evaluate the potential of hUC-MSCs in the treatment of DFU. The diabetic rat model was established by streptozotocin injection, which was used to create full-thickness foot dorsal skin wounds to mimic DFU by a 6-mm skin biopsy punch and a Westcott scissor. The hUC-MSCs were transplanted through femoral vein, and the ulcer cicatrization situation and the fate of hUC-MSCs were evaluated. Our data suggest that intravenously transplantated hUC-MSCs have the ability to migrate and locate to the wound tissue and are helpful to wound healing in DFU rats, partly by regulating inflammation, trans-differentiation and providing growth factors that promote angiogenesis, cell proliferation and collagen deposition. Herein, we demonstrate that hUC-MSC transplantation is able to accelerate DFU healing in rats and transplantation of exogenous stem cells may be a potential strategy for clinical application in DFUs.

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          Most cited references28

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          Mesenchymal stem cells in the Wharton's jelly of the human umbilical cord.

          The Wharton's jelly of the umbilical cord contains mucoid connective tissue and fibroblast-like cells. Using flow cytometric analysis, we found that mesenchymal cells isolated from the umbilical cord express matrix receptors (CD44, CD105) and integrin markers (CD29, CD51) but not hematopoietic lineage markers (CD34, CD45). Interestingly, these cells also express significant amounts of mesenchymal stem cell markers (SH2, SH3). We therefore investigated the potential of these cells to differentiate into cardiomyocytes by treating them with 5-azacytidine or by culturing them in cardiomyocyte-conditioned medium and found that both sets of conditions resulted in the expression of cardiomyocyte markers, namely N-cadherin and cardiac troponin I. We also showed that these cells have multilineage potential and that, under suitable culture conditions, are able to differentiate into cells of the adipogenic and osteogenic lineages. These findings may have a significant impact on studies of early human cardiac differentiation, functional genomics, pharmacological testing, cell therapy, and tissue engineering by helping to eliminate worrying ethical and technical issues.
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            Concise review: role of mesenchymal stem cells in wound repair.

            Wound healing requires a coordinated interplay among cells, growth factors, and extracellular matrix proteins. Central to this process is the endogenous mesenchymal stem cell (MSC), which coordinates the repair response by recruiting other host cells and secreting growth factors and matrix proteins. MSCs are self-renewing multipotent stem cells that can differentiate into various lineages of mesenchymal origin such as bone, cartilage, tendon, and fat. In addition to multilineage differentiation capacity, MSCs regulate immune response and inflammation and possess powerful tissue protective and reparative mechanisms, making these cells attractive for treatment of different diseases. The beneficial effect of exogenous MSCs on wound healing was observed in a variety of animal models and in reported clinical cases. Specifically, they have been successfully used to treat chronic wounds and stimulate stalled healing processes. Recent studies revealed that human placental membranes are a rich source of MSCs for tissue regeneration and repair. This review provides a concise summary of current knowledge of biological properties of MSCs and describes the use of MSCs for wound healing. In particular, the scope of this review focuses on the role MSCs have in each phase of the wound-healing process. In addition, characterization of MSCs containing skin substitutes is described, demonstrating the presence of key growth factors and cytokines uniquely suited to aid in wound repair.
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              Mesenchymal Stromal Cells: Current Understanding and Clinical Status

              Multipotent mesenchymal stromal cells (MSCs) represent a rare heterogeneous subset of pluripotent stromal cells that can be isolated from many different adult tissues that exhibit the potential to give rise to cells of diverse lineages. Numerous studies have reported beneficial effects of MSCs in tissue repair and regeneration. After culture expansion and in vivo administration, MSCs home to and engraft to injured tissues and modulate the inflammatory response through synergistic downregulation of proinflammatory cytokines and upregulation of both prosurvival and antiinflammatory factors. In addition, MSCs possess remarkable immunosuppressive properties, suppressing T-cell, NK cell functions, and also modulating dentritic cell activities. Tremendous progress has been made in preclinical studies using MSCs, including the ability to use allogeneic cells, which has driven the application of MSCs toward the clinical setting. This review highlights our current understanding into the biology of MSCs with particular emphasis on the cardiovascular and renal applications, and provides a brief update on the clinical status of MSC-based therapy.
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                Author and article information

                Journal
                Acta Biochim Biophys Sin (Shanghai)
                Acta Biochim. Biophys. Sin. (Shanghai)
                abbs
                Acta Biochimica et Biophysica Sinica
                Oxford University Press
                1672-9145
                1745-7270
                June 2020
                02 June 2020
                02 June 2020
                : 52
                : 6
                : 620-630
                Affiliations
                [1 ]Department of Interventional Radiology, Affiliated Hospital of Nantong University , Nantong 226001, China
                [2 ]Department of Interventional & Vascular Surgery, Shanghai Tenth People’s Hospital, Tongji University , School of Medicine, Shanghai 200072, China
                [3 ]Institute of Medical Intervention Engineering, Tongji University , Shanghai 200072, China
                [4 ]Shanghai Public Health Clinical Center, Fudan University , Shanghai 201508, China
                Author notes
                Correspondence address. Tel/Fax: +86-21-66301045, E-mail: cjr.limaoquan1965@ 123456vip.163.com (M.L.) / Tel/Fax: +86-513-85052201; E-mail: zhaohui8868@ 123456sina.com (H.Z.)

                Rongfeng Shi, Weishuai Lian and Yinpeng Jin These authors contributed equally to this work.

                Article
                gmaa039
                10.1093/abbs/gmaa039
                7333920
                32484226
                e2f10ac2-8722-42ef-b178-d12d7120228d
                © The Author(s) 2020. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 4 November 2019
                : 15 January 2020
                : 31 March 2020
                : 20 January 2020
                Page count
                Pages: 11
                Funding
                Funded by: Science Foundation of China Postdoctoral
                Award ID: 2019M651928
                Funded by: Natural Science Foundation of Nantong City
                Award ID: MS12018068
                Funded by: Natural Science Foundation of Jiangsu Province of China
                Award ID: BK20180946
                Categories
                Original Article

                human umbilical cord mesenchymal stem cells,diabetic foot ulcer,tissue repair

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