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      Silk fibroin scaffolds seeded with Wharton’s jelly mesenchymal stem cells enhance re-epithelialization and reduce formation of scar tissue after cutaneous wound healing

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          Abstract

          Background

          The treatment of extensive and/or chronic skin wounds is a widespread and costly public health problem. Mesenchymal stem cells (MSCs) have been proposed as a potential cell therapy for inducing wound healing in different clinical settings, alone or in combination with biosynthetic scaffolds. Among them, silk fibroin (SF) seeded with MSCs has been shown to have increased efficacy in skin wound healing experimental models.

          Methods

          In this report, we investigated the wound healing effects of electrospun SF scaffolds cellularized with human Wharton’s jelly MSCs (Wj-MSCs-SF) using a murine excisional wound splinting model.

          Results

          Immunohistopathological examination after transplant confirmed the presence of infiltrated human fibroblast-like CD90-positive cells in the dermis of the Wj-MSCs-SF-treated group, yielding neoangiogenesis, decreased inflammatory infiltrate and myofibroblast proliferation, less collagen matrix production, and complete epidermal regeneration.

          Conclusions

          These findings indicate that Wj-MSCs transplanted in the wound bed on a silk fibroin scaffold contribute to the generation of a well-organized and vascularized granulation tissue, enhance reepithelization of the wound, and reduce the formation of fibrotic scar tissue, highlighting the potential therapeutic effects of Wj-MSC-based tissue engineering approaches to non-healing wound treatment.

          Electronic supplementary material

          The online version of this article (10.1186/s13287-019-1229-6) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          Adult mesenchymal stem cells for tissue engineering versus regenerative medicine.

          Adult mesenchymal stem cells (MSCs) can be isolated from bone marrow or marrow aspirates and because they are culture-dish adherent, they can be expanded in culture while maintaining their multipotency. The MSCs have been used in preclinical models for tissue engineering of bone, cartilage, muscle, marrow stroma, tendon, fat, and other connective tissues. These tissue-engineered materials show considerable promise for use in rebuilding damaged or diseased mesenchymal tissues. Unanticipated is the realization that the MSCs secrete a large spectrum of bioactive molecules. These molecules are immunosuppressive, especially for T-cells and, thus, allogeneic MSCs can be considered for therapeutic use. In this context, the secreted bioactive molecules provide a regenerative microenvironment for a variety of injured adult tissues to limit the area of damage and to mount a self-regulated regenerative response. This regenerative microenvironment is referred to as trophic activity and, therefore, MSCs appear to be valuable mediators for tissue repair and regeneration. The natural titers of MSCs that are drawn to sites of tissue injury can be augmented by allogeneic MSCs delivered via the bloodstream. Indeed, human clinical trials are now under way to use allogeneic MSCs for treatment of myocardial infarcts, graft-versus-host disease, Crohn's Disease, cartilage and meniscus repair, stroke, and spinal cord injury. This review summarizes the biological basis for the in vivo functioning of MSCs through development and aging.
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            Electrospun nanofibrous structure: A novel scaffold for tissue engineering

            The architecture of an engineered tissue substitute plays an important role in modulating tissue growth. A novel poly(D,L-lactide-co-glycolide) (PLGA) structure with a unique architecture produced by an electrospinning process has been developed for tissue-engineering applications. Electrospinning is a process whereby ultra-fine fibers are formed in a high-voltage electrostatic field. The electrospun structure, composed of PLGA fibers ranging from 500 to 800 nm in diameter, features a morphologic similarity to the extracellular matrix (ECM) of natural tissue, which is characterized by a wide range of pore diameter distribution, high porosity, and effective mechanical properties. Such a structure meets the essential design criteria of an ideal engineered scaffold. The favorable cell-matrix interaction within the cellular construct supports the active biocompatibility of the structure. The electrospun nanofibrous structure is capable of supporting cell attachment and proliferation. Cells seeded on this structure tend to maintain phenotypic shape and guided growth according to nanofiber orientation. This novel biodegradable scaffold has potential applications for tissue engineering based upon its unique architecture, which acts to support and guide cell growth. Copyright 2002 Wiley Periodicals, Inc. J Biomed Mater Res 60: 613-621, 2002
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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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                Author and article information

                Contributors
                jeduardo.millan@um.es
                cmmarti@um.es
                paodunromec@gmail.com
                sdac1@um.es
                marina.carpes@imib.es
                josel.cenis@carm.es
                jmoraled@um.es
                ntma@um.es
                00-34-868888497 , david.garcia23@um.es
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                27 April 2019
                27 April 2019
                2019
                : 10
                : 126
                Affiliations
                [1 ]Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria-Arrixaca, Virgen de la Arrixaca University Hospital, University of Murcia, Murcia, Spain
                [2 ]ISNI 0000 0001 2287 8496, GRID grid.10586.3a, Internal Medicine Department, Medicine School, , University of Murcia, ; Avenida Buenavista s/n. El Palmar, Murcia, Spain
                [3 ]GRID grid.452553.0, Experimental Pathology Unit, , Instituto Murciano de Investigación Biosanitaria (IMIB)-Arrixaca, ; Murcia, Spain
                [4 ]Biotechnology Department, Instituto Murciano de Investigación y Desarrollo Agrario y Alimentario (IMIDA), Murcia, Spain
                [5 ]ISNI 0000 0001 2287 8496, GRID grid.10586.3a, Physiology Department, Medicine School, , University of Murcia, ; Murcia, Spain
                Author information
                http://orcid.org/0000-0001-6610-8442
                Article
                1229
                10.1186/s13287-019-1229-6
                6487033
                31029166
                d0ce7308-480c-45f2-85a2-93e5b06133f4
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 16 January 2019
                : 25 March 2019
                : 3 April 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004587, Instituto de Salud Carlos III;
                Award ID: RD16/0011/0001
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Molecular medicine
                mesenchymal stem cells,wharton’s jelly,wound healing,silk fibroin
                Molecular medicine
                mesenchymal stem cells, wharton’s jelly, wound healing, silk fibroin

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