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      Hypoxic Conditioned Medium from Human Amniotic Fluid-Derived Mesenchymal Stem Cells Accelerates Skin Wound Healing through TGF-β/SMAD2 and PI3K/Akt Pathways

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          Abstract

          In a previous study, we isolated human amniotic fluid (AF)-derived mesenchymal stem cells (AF-MSCs) and utilized normoxic conditioned medium (AF-MSC-norCM) which has been shown to accelerate cutaneous wound healing. Because hypoxia enhances the wound healing function of mesenchymal stem cell-conditioned medium (MSC-CM), it is interesting to explore the mechanism responsible for the enhancement of wound healing function. In this work, hypoxia not only increased the proliferation of AF-MSCs but also maintained their constitutive characteristics (surface marker expression and differentiation potentials). Notably, more paracrine factors, VEGF and TGF-β1, were secreted into hypoxic conditioned medium from AF-MSCs (AF-MSC-hypoCM) compared to AF-MSC-norCM. Moreover, AF-MSC-hypoCM enhanced the proliferation and migration of human dermal fibroblasts in vitro, and wound closure in a skin injury model, as compared to AF-MSC-norCM. However, the enhancement of migration of fibroblasts accelerated by AF-MSC-hypoCM was inhibited by SB505124 and LY294002, inhibitors of TGF-β/SMAD2 and PI3K/AKT, suggesting that AF-MSC-hypoCM-enhanced wound healing is mediated by the activation of TGF-β/SMAD2 and PI3K/AKT. Therefore, AF-MSC-hypoCM enhances wound healing through the increase of hypoxia-induced paracrine factors via activation of TGF-β/SMAD2 and PI3K/AKT pathways.

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          Wound healing--aiming for perfect skin regeneration.

          P. Martin (1997)
          The healing of an adult skin wound is a complex process requiring the collaborative efforts of many different tissues and cell lineages. The behavior of each of the contributing cell types during the phases of proliferation, migration, matrix synthesis, and contraction, as well as the growth factor and matrix signals present at a wound site, are now roughly understood. Details of how these signals control wound cell activities are beginning to emerge, and studies of healing in embryos have begun to show how the normal adult repair process might be readjusted to make it less like patching up and more like regeneration.
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            Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone.

            E Horwitz, P L Gordon, W. K. K. Koo … (2002)
            Treatment with isolated allogeneic mesenchymal cells has the potential to enhance the therapeutic effects of conventional bone marrow transplantation in patients with genetic disorders affecting mesenchymal tissues, including bone, cartilage, and muscle. To demonstrate the feasibility of mesenchymal cell therapy and to gain insight into the transplant biology of these cells, we used gene-marked, donor marrow-derived mesenchymal cells to treat six children who had undergone standard bone marrow transplantation for severe osteogenesis imperfecta. Each child received two infusions of the allogeneic cells. Five of six patients showed engraftment in one or more sites, including bone, skin, and marrow stroma, and had an acceleration of growth velocity during the first 6 mo postinfusion. This improvement ranged from 60% to 94% (median, 70%) of the predicted median values for age- and sex-matched unaffected children, compared with 0% to 40% (median, 20%) over the 6 mo immediately preceding the infusions. There was no clinically significant toxicity except for an urticarial rash in one patient just after the second infusion. Failure to detect engraftment of cells expressing the neomycin phosphotransferase marker gene suggested the potential for immune attack against therapeutic cells expressing a foreign protein. Thus, allogeneic mesenchymal cells offer feasible posttransplantation therapy for osteogenesis imperfecta and likely other disorders originating in mesenchymal precursors.
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              Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms.

              T Kinnaird, E STABILE, M. Burnett … (2004)
              We recently demonstrated that marrow stromal cells (MSCs) augment collateral remodeling through release of several cytokines such as VEGF and bFGF rather than via cell incorporation into new or remodeling vessels. The present study was designed to characterize the full spectrum of cytokine genes expressed by MSCs and to further examine the role of paracrine mechanisms that underpin their therapeutic potential. Normal human MSCs were cultured under normoxic or hypoxic conditions for 72 hours. The gene expression profile of the cells was determined using Affymetrix GeneChips representing 12 000 genes. A wide array of arteriogenic cytokine genes were expressed at baseline, and several were induced >1.5-fold by hypoxic stress. The gene array data were confirmed using ELISA assays and immunoblotting of the MSC conditioned media (MSC(CM)). MSC(CM) promoted in vitro proliferation and migration of endothelial cells in a dose-dependent manner; anti-VEGF and anti-FGF antibodies only partially attenuated these effects. Similarly, MSC(CM) promoted smooth muscle cell proliferation and migration in a dose-dependent manner. Using a murine hindlimb ischemia model, murine MSC(CM) enhanced collateral flow recovery and remodeling, improved limb function, reduced the incidence of autoamputation, and attenuated muscle atrophy compared with control media. These data indicate that paracrine signaling is an important mediator of bone marrow cell therapy in tissue ischemia, and that cell incorporation into vessels is not a prerequisite for their effects.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Sci
                Journal ID (iso-abbrev): Int J Mol Sci
                Journal ID (publisher-id): ijms
                Title: International Journal of Molecular Sciences
                Publisher: Molecular Diversity Preservation International (MDPI)
                ISSN (Electronic): 1422-0067
                Publication date Collection: January 2014
                Publication date (Electronic): 06 January 2014
                Volume: 15
                Issue: 1
                Pages: 605-628
                Affiliations
                [1 ]Laboratory of Cell Function Regulation, College of Life Sciences and Biotechnology, Korea University, Seoul 136-717, Korea; E-Mails: ek-young@ 123456hanmail.net (E.K.J.); qkzhang0915@ 123456gmail.com (Q.Z.); biosun302@ 123456korea.ac.kr (B.S.Y.); moonjaihi@ 123456hanmail.net (J.-H.M.); ggang1979@ 123456hanmail.net (G.L.); legnaym@ 123456korea.ac.kr (G.P.); rebeast@ 123456korea.ac.kr (P.J.K.); ano112@ 123456nate.com (J.H.L.)
                [2 ]Department of Pathology, College of Medicine, Korea University Guro Hospital, Seoul 152-703, Korea; E-Mail: ark@ 123456korea.ac.kr
                Author notes
                [†]

                These authors contributed equally to this work.

                [* ]Author to whom correspondence should be addressed; E-Mail: bioseung@ 123456korea.ac.kr ; Tel./Fax: +82-2-3290-3057.
                Article
                Publisher ID: ijms-15-00605
                DOI: 10.3390/ijms15010605
                PMC ID: 3907828
                PubMed ID: 24398984
                SO-VID: 841ea1ae-1790-4fd5-90dd-e8e112d088d5
                Copyright © © 2014 by the authors; licensee MDPI, Basel, Switzerland
                License:

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

                History
                Date received : 12 November 2013
                Date revision received : 21 December 2013
                Date accepted : 02 January 2014
                Categories
                Subject: Article

                ScienceOpen disciplines: Molecular biology
                Keywords: tgf-β/smad2,amniotic fluid-derived mesenchymal stem cells (af-mscs),hypoxia,pi3k/akt,wound healing
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: tgf-β/smad2, amniotic fluid-derived mesenchymal stem cells (af-mscs), hypoxia, pi3k/akt, wound healing

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