Hypoxic ucMSC-secreted exosomal miR-125b promotes endothelial cell survival and migration during wound healing by targeting TP53INP1

Abstract

A hypoxic microenvironment is a common feature of skin wounds. Our previous study demonstrated that three-dimensional coculture of umbilical cord-derived mesenchymal stem cells (ucMSCs) and endothelial cells facilitates cell communication and host integration in skin tissue engineering. Here, we aimed to identify the mechanism by which ucMSCs affect endothelial cells under hypoxic conditions after skin injury. We demonstrate that hypoxia enhances the exosome-mediated paracrine function of ucMSCs, which increases endothelial cell proliferation and migration. In a mouse full-thickness skin injury model, ucMSC-derived exosomes can be taken up by endothelial cells and accelerate wound healing. Hypoxic exosomes lead to a better outcome than normoxic exosomes by promoting proliferation and inhibiting apoptosis. Mechanistically, microRNA-125b (miR-125b) transcription is induced by hypoxia in ucMSCs. After being packaged into hypoxic exosomes and transported to endothelial cells, miR-125b targets and suppresses the expression of tumor protein p53 inducible nuclear protein 1 (TP53INP1) and alleviates hypoxia-induced cell apoptosis. Inhibition of miR-125b-TP53INP1 interaction attenuates the protective effect of hypoxic exosomes. Moreover, artificial agomiR-125b can accelerate wound healing in vivo. Our findings reveal communication between ucMSCs and endothelial cells via exosomal miR-125b/TP53INP1 signaling in the hypoxic microenvironment and present hypoxic exosomes as a promising therapeutic strategy to enhance cutaneous repair. A hypoxic microenvironment is a common feature of skin wounds. Our previous study demonstrated that three-dimensional coculture of umbilical cord-derived mesenchymal stem cells (ucMSCs) and endothelial cells facilitates cell communication and host integration in skin tissue engineering. Here, we aimed to identify the mechanism by which ucMSCs affect endothelial cells under hypoxic conditions after skin injury. We demonstrate that hypoxia enhances the exosome-mediated paracrine function of ucMSCs, which increases endothelial cell proliferation and migration. In a mouse full-thickness skin injury model, ucMSC-derived exosomes can be taken up by endothelial cells and accelerate wound healing. Hypoxic exosomes lead to a better outcome than normoxic exosomes by promoting proliferation and inhibiting apoptosis. Mechanistically, microRNA-125b (miR-125b) transcription is induced by hypoxia in ucMSCs. After being packaged into hypoxic exosomes and transported to endothelial cells, miR-125b targets and suppresses the expression of tumor protein p53 inducible nuclear protein 1 (TP53INP1) and alleviates hypoxia-induced cell apoptosis. Inhibition of miR-125b-TP53INP1 interaction attenuates the protective effect of hypoxic exosomes. Moreover, artificial agomiR-125b can accelerate wound healing in vivo. Our findings reveal communication between ucMSCs and endothelial cells via exosomal miR-125b/TP53INP1 signaling in the hypoxic microenvironment and present hypoxic exosomes as a promising therapeutic strategy to enhance cutaneous repair. IntroductionSkin, an effective barrier that prevents body dehydration and external microorganism penetration, is extremely vulnerable to different types of lesions, such as burns, ulcers, and wounds. Stem cell-based skin tissue engineering has shown great promise for wound healing.1Nourian Dehkordi A. Mirahmadi Babaheydari F. Chehelgerdi M. Raeisi Dehkordi S. Skin tissue engineering: wound healing based on stem-cell-based therapeutic strategies.Stem Cell Res. Ther. 2019; 10: 111Crossref PubMed Scopus (147) Google Scholar, 2Petrof G. Abdul-Wahab A. McGrath J.A. Cell therapy in dermatology.Cold Spring Harb. Perspect. Med. 2014; 4: a015156Crossref PubMed Scopus (19) Google Scholar, 3Sun B.K. Siprashvili Z. Khavari P.A. Advances in skin grafting and treatment of cutaneous wounds.Science. 2014; 346: 941-945Crossref PubMed Scopus (393) Google Scholar Mesenchymal stem cells (MSCs) exist in many adult tissues, such as the bone marrow, adipose tissue, and umbilical cords (UCs).4Pereira R.F. Barrias C.C. Granja P.L. Bartolo P.J. Advanced biofabrication strategies for skin regeneration and repair.Nanomedicine (Lond.). 2013; 8: 603-621Crossref PubMed Scopus (207) Google Scholar Among the types of MSCs, umbilical cord MSCs (ucMSCs) are advantageous because their collection causes no risk or discomfort to the donor, and they have a highly similar gene expression pattern to that of skin fibroblasts;5Schneider R.K. Püllen A. Kramann R. Bornemann J. Knüchel R. Neuss S. Perez-Bouza A. Long-term survival and characterisation of human umbilical cord-derived mesenchymal stem cells on dermal equivalents.Differentiation. 2010; 79: 182-193Crossref PubMed Scopus (54) Google Scholar,6Chen D. Hao H. Tong C. Liu J. Dong L. Ti D. Hou Q. Liu H. Han W. Fu X. Transdifferentiation of Umbilical Cord-Derived Mesenchymal Stem Cells Into Epidermal-Like Cells by the Mimicking Skin Microenvironment.Int. J. Low. Extrem. Wounds. 2015; 14: 136-145Crossref PubMed Scopus (11) Google Scholar thus, ucMSCs have a substantial potential in skin wound repair or tissue engineering. However, the clinical application of ucMSCs still faces several problems, such as the low cell viability of transplanted cells and the risk of immune responses in recipients.7Kurtz A. Mesenchymal stem cell delivery routes and fate.Int. J. Stem Cells. 2008; 1: 1-7Crossref PubMed Scopus (177) Google ScholarExosomes (Exos) derived from MSCs exhibit similar functions to MSCs, but have their own of such as their and X. F. L. L. G. J. J. Hypoxic exosomal of cells via 2019; PubMed Scopus Google H. G. of to for 2019; PubMed Scopus Google Scholar are and R. and of PubMed Scopus Google 2019; PubMed Scopus Google Scholar and to or cells, exosomes an in communication and R. and of PubMed Scopus Google 2019; PubMed Scopus Google Scholar of exosomes is an to tissue repair and M. M. C. Mesenchymal Stem Cell by Google Scholar, J. S. C. M. of for 14: PubMed Scopus Google Scholar, G. R. P.A. S. the of PubMed Scopus Google Scholar However, the of exosomes to the cells from which they are derived and is by and such as or or M. M. A. microenvironment by cells after PubMed Scopus Google Scholar, R. A. M. W. in for in PubMed Scopus Google Scholar, M. W. A. R. H. J. H. H. X. Hou H. X. Hypoxic exosomes tumor and PubMed Scopus Google Scholar skin a of hypoxia exosomes by ucMSCs under hypoxic conditions are different from under normoxic the of types of and S. C. C. C. H. X. M. Cord-Derived Mesenchymal Stem by the Cells Med. PubMed Scopus Google J. J. H. from human umbilical cord accelerate cutaneous wound healing of and 8: PubMed Scopus Google Scholar However, hypoxic ucMSC-derived exosomes have a function in skin wound healing to be cells a in skin repair. hypoxic in enhances the proliferation and of endothelial cells to J. G. and in PubMed Scopus Google and gene therapy for the delivery of to and in wound PubMed Scopus Google Scholar We ucMSCs and endothelial cells in a three-dimensional to skin We that three-dimensional coculture of the types of cells the gene expression of and in and host integration in of ucMSCs or endothelial cells that communication be to and tissue X. J. G. X. of mesenchymal stem cells and endothelial cells enhances host tissue integration and in skin PubMed Scopus Google Scholar that a hypoxic for cells, we that the communication between ucMSCs and endothelial cells under hypoxic conditions be a for skin we that hypoxia the paracrine effect of ucMSCs on endothelial cell proliferation and in and the of ucMSCs on endothelial cells by exosomes. Mechanistically, miR-125b in hypoxic exosomes a that the survival and of endothelial Our study that signaling is for the communication of ucMSCs and endothelial cells, which a therapeutic for skin tissue exosomes the paracrine effect of ucMSCs on the cell proliferation and of endothelial cells under hypoxic the of hypoxia in the interaction of ucMSCs and endothelial cells, we human umbilical endothelial cells the from ucMSCs under normoxic or hypoxic from the Cell that the normoxic and hypoxic of ucMSCs the viability of and the hypoxic in cell viability than the normoxic of endothelial cells an in tissue repair. study the effect of the hypoxic of ucMSCs on we wound healing and demonstrated that the hypoxic of ucMSCs cell as by the wound in the hypoxic than in the normoxic an coculture a to the hypoxic of ucMSCs the the of cells that hypoxia the paracrine effect of ucMSCs on the proliferation and of endothelial as paracrine of mesenchymal stem cells, communication in or S. Mesenchymal Stem Ther. 2015; PubMed Scopus Google Scholar, J. J. R. J. Q. J. Mesenchymal stem via of Cell Res. Ther. PubMed Scopus Google Scholar, for Cells. PubMed Scopus Google Scholar the of exosomes in the paracrine function of ucMSCs, we ucMSCs an of and for by and the cells to hypoxic conditions for the to that the promoting effect of ucMSCs on the of that exosomes are an of ucMSCs for under normoxic and hypoxic and normoxic and hypoxic exosomes from the by and potential of the normoxic and hypoxic exosomes by a In the of of the of the types of exosomes and the potential from the types of exosomes which previous for Cells. 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R. of into 2019; 8: PubMed Scopus Google C. F. C. R. M. M. to exosomes and to 2014; 8: PubMed Scopus Google Scholar Hypoxic conditions have in the expression of in different types of cells as as in the exosomes derived from A. G. in tumor microenvironment and PubMed Scopus Google Scholar, M. Liu H. exosomal expression the between cells and in 2019; PubMed Scopus Google Scholar, M. L. C.C. mesenchymal stem exosomes facilitates repair of cell in 8: PubMed Scopus Google Scholar A previous study the exosomal expression in ucMSCs and several and S. C. C. C. H. X. M. Cord-Derived Mesenchymal Stem by the Cells Med. PubMed Scopus Google Scholar We that the of in exosomes for their we the expression of and their expression between hypoxic exosomes and normoxic exosomes from ucMSCs by expression of miR-125b to be in hypoxic exosomes normoxic exosomes the of the miR-125b in exosomes and their ucMSCs, we the expression of miR-125b in ucMSCs to hypoxic a for and or to a hypoxia We an of miR-125b expression in ucMSCs under hypoxic conditions and A of the miR-125b under hypoxic conditions that the of miR-125b in exosomes to in ucMSCs under hypoxic exosomal miR-125b cell and survival of endothelial cells under hypoxic of and in or from ucMSCs. no and miR-125b in ucMSCs into and to hypoxia for 1 and or treatment for to the of miR-125b in ucMSCs to for expression of miR-125b in an for and or for of proliferation the and of of after different of the of the exosomes or of are as the exosomal miR-125b be taken up by endothelial cells, we normoxic exosomes or hypoxic exosomes for and the an for the previous we the expression of miR-125b in the treatment the expression of miR-125b in the of that the in miR-125b expression in to their from exosomes than the transcription of miR-125b in the in miR-125b expression in hypoxic as shown in the of miR-125b expression in hypoxic than that in normoxic the of exosomes in endothelial cells demonstrated by of miR-125b from hypoxic exosomes than of miR-125b from normoxic exosomes the function of exosomes on we hypoxic exosomes or miR-125b and of miR-125b the promoting effect of hypoxic exosomes on cell and migration. the in study and hypoxic treatment the cell induced by of of miR-125b the protective effect of hypoxic exosomes on cell we demonstrated that ucMSC-derived exosomal transcription induced by hypoxic for cell and survival of endothelial interaction of miR-125b and is for the function of hypoxic in signaling by their the mechanism of exosomal miR-125b in endothelial cells, we the targets of miR-125b and and common targets that targets in the cell and tumor protein p53 inducible nuclear protein 1 (TP53INP1) an of and the of miR-125b to the of the expression of by and and protein of in endothelial cells by to hypoxia and the of in hypoxia-induced cell miR-125b the of under normoxic and hypoxic and that miR-125b the of and miR-125b targets in endothelial targets of miR-125b in of common targets of between and of the of in miR-125b or and and protein of in the under normoxic or hypoxic for and protein of in the of the protein of and in the and protein of in the exosomes or under normoxic or hypoxic for of proliferation the and of of after different of the of after different of are as the study the interaction of miR-125b and we or a delivery we the of the interaction of miR-125b and in the of endothelial cell by the protein of and cell cell protein and cell of miR-125b the of and and the of in of of the the effect of miR-125b on the protein Moreover, of miR-125b and expression and of the effect of miR-125b on cell that the function of miR-125b hypoxia in to the of expression identify the protective effect of hypoxic exosomes on endothelial cells on we the and protein of Hypoxic treatment the of of miR-125b effect under hypoxic conditions cell and survival under normoxic and hypoxic to cell viability than the Hypoxic treatment cell the protective effect by A similar in the hypoxic exosomes the of cells, the promoting effect of hypoxic exosomes hypoxia of endothelial cells to hypoxia we a cell in hypoxic cells than in hypoxic cells that exosomal miR-125b in endothelial cells and that the interaction of miR-125b and for the function of miR-125b cutaneous wound the function of miR-125b in skin wound repair in we agomiR-125b or into the to skin injury by the to an in and the wound of the agomiR-125b than that of the as shown in to a in the of the of that of the of but the of cells and the of cells agomiR-125b treatment expression of and we a in in the agomiR-125b the of miR-125b and in the wound of or the of injury repair by and the that the expression of miR-125b no in the of the expression in the or the interaction of miR-125b and exosome-mediated skin tissue enhances cutaneous wound of wound of or the of wound wound and are a and a to the in the of of and of wound from to the of the the of cells, the of cells, and the of in and in and no of miR-125b and in wound of the exosomes or are as the have the effect of MSCs in the repair of or clinical of the of MSCs in to the low survival and responses by X. Han S. H. for and for bone 2019; PubMed Scopus Google Scholar, M. A. H. Stem Cell A for PubMed Scopus Google Scholar, H. H. R.K. A. R. M. A. therapeutic potential of human mesenchymal stem cells in a mouse PubMed Scopus Google Scholar by MSCs a in and has that exosomes can be as effective in tissue they and proliferation and similar to their D. H. X. A. M. A for Ther. PubMed Scopus Google Scholar, C. C. J. R. G. the of in an Ther. PubMed Scopus Google Scholar, M. A. A. H. of exosomes in and in and PubMed Scopus Google Scholar, M. A. R. H. Mesenchymal stem a therapeutic to Cell Res. Ther. 2019; 10: PubMed Scopus Google Scholar the of exosomes are is to the cell of to the of MSCs, and to the mechanism by which exosomes function in the present ucMSCs to their similar gene expression to that of skin and their R.K. Püllen A. Kramann R. Bornemann J. Knüchel R. Neuss S. Perez-Bouza A. Long-term survival and characterisation of human umbilical cord-derived mesenchymal stem cells on dermal equivalents.Differentiation. 2010; 79: 182-193Crossref PubMed Scopus (54) Google Scholar,6Chen D. Hao H. Tong C. Liu J. Dong L. Ti D. Hou Q. Liu H. Han W. Fu X. Transdifferentiation of Umbilical Cord-Derived Mesenchymal Stem Cells Into Epidermal-Like Cells by the Mimicking Skin Microenvironment.Int. J. Low. Extrem. Wounds. 2015; 14: 136-145Crossref PubMed Scopus (11) Google Scholar normoxic and hypoxic exosomes derived from ucMSCs the of endothelial cells and wound that ucMSCs as a cell for exosomes in skin We have that ucMSCs endothelial cells and enhance the function of X. J. G. X. of mesenchymal stem cells and endothelial cells enhances host tissue integration and in skin PubMed Scopus Google Scholar Here, we that the protective paracrine effect of ucMSCs on endothelial cells by as by the of function of ucMSCs after In demonstrated that exosomes derived from ucMSCs wound which is previous S. C. C. C. H. X. M. Cord-Derived Mesenchymal Stem by the Cells Med. PubMed Scopus Google J. J. H. from human umbilical cord accelerate cutaneous wound healing of and 8: PubMed Scopus Google have demonstrated that hypoxic exosomes enhance cell proliferation and or tumor M. L. C.C. mesenchymal stem exosomes facilitates repair of cell in 8: PubMed Scopus Google X. F. Hypoxic and by Ther. 2019; PubMed Scopus Google P.L. Hypoxic exosomal and by and protein PubMed Scopus Google Scholar In the present we that hypoxic exosomes endothelial cell proliferation and in the of skin and a proliferation and their effect on the wound to that of normoxic exosomes. However, are several to the present study on the communication of exosomes endothelial In or in skin cell cells and present in the and a or interaction of cells which be in In we that no in the normoxic hypoxic or which that the of exosomes on is the of the is the effect of exosomes on the cells and and which in an to the of Our study is to the protective effect of exosomes on endothelial In the of exosomes on the of and be In is that is an to the of in we the effect of the types of exosomes after healing and their on the of and the of wound repair is that wound healing in a mouse is different from that of as via X. J. mouse wound model, for stem cell 2013; 8: PubMed Scopus Google Scholar A the of or a full-thickness skin injury better the conditions of human skin X. J. mouse wound model, for stem cell 2013; 8: PubMed Scopus Google and hypoxia in of or of be the of the hypoxic conditions we a of miR-125b expression under miR-125b expression a low of induced expression of miR-125b than a of effect of hypoxic exosomes under different hypoxic conditions in present be for cell to exosomes to of low of and better of the of is to the hypoxic conditions and the functions of hypoxic exosomes under different hypoxic have shown that exosomes cells by study the expression of exosomes derived from ucMSCs or human cells, and as the of and S. C. C. C. H. X. M. Cord-Derived Mesenchymal Stem by the Cells Med. PubMed Scopus Google Scholar We that the of in exosomes for their and we the highly and their in exosomes from ucMSCs under normoxic and hypoxic We a in the miR-125b in hypoxic exosomes from ucMSCs. miR-125b has to be in derived mesenchymal stem exosomes after to M. L. C.C. mesenchymal stem exosomes facilitates repair of cell in 8: PubMed Scopus Google Scholar which that hypoxia-induced of miR-125b in exosomes be a common in of in exosomes their expression in their cells of J. R. of into 2019; 8: PubMed Scopus Google C. F. C. R. M. M. to exosomes and to 2014; 8: PubMed Scopus Google Scholar We the expression of miR-125b in ucMSCs and cells and that the miR-125b in ucMSCs than that in cells in a to hypoxia induced miR-125b expression in ucMSCs and cells the but the the of miR-125b or to exosomes hypoxia is to the function of exosomes from different cell under as as the to a for their clinical is a protein functions and is in cell and apoptosis. In the present we that hypoxia the of in hypoxia-induced cell is a of miR-125b in or cell such as and cell Q. H. and p53 PubMed Scopus Google F. Liu Q. X. H. X. proliferation and of cells tumor in and in PubMed Scopus Google Scholar However, interaction between exosomal miR-125b and in cells to be We that the of cell proliferation and and the of cell by exosomal miR-125b on interaction that an of of miR-125b or wound in expression in an interaction of miR-125b and the miR-125b-TP53INP1 interaction for the function of endothelial we that of miR-125b expression the protective effect of hypoxic exosomes in in Our in study that the of miR-125b in wound exosomes than in agomiR-125b which be by such as the of miR-125b in exosomes and agomiR-125b protective of such as and S. C. C. C. H. X. M. Cord-Derived Mesenchymal Stem by the Cells Med. PubMed Scopus Google Scholar or better of exosomes in vivo. a better effect of exosomes than In exosomes or in be in a cutaneous repair to their different therapeutic we demonstrated that hypoxic exosomes from ucMSCs skin wound repair by promoting cell and and cell apoptosis. Mechanistically, transcription induced by into exosomes in ucMSCs. After by endothelial cells, miR-125b the of and cell which to cell survival and wound and by the and of in an and the full-thickness skin wound model, by of A skin wound in on the In into normoxic or hypoxic in and agomiR-125b or in exosomes or the wound and the wound by after and skin for on a the of the wound between and to wound and in in into and of skin by the skin from to for and to cell proliferation and the of to cell to the and to a of and cells and in for and cell by for and for to exosomes. and potential of exosomes by of exosomes exosomes for their protein the protein exosomes a for and for in normoxic and hypoxic conditions for and by skin endothelial cells, exosomes into the of after skin and into and of exosomes into skin endothelial cells by and in in and hypoxic cells to and for in a cells a of for to cell and low of to the of exosomes of by to of and miR-125b cell coculture of exosomes and cells, of exosomes for viability to proliferation and a of in and of to of the and for 1 Cell viability a a of in by in Cells a of cells and for by a cell cells from ucMSCs or hypoxic of a and of the cells in and into the of or exosomes to the After the cells on the of the cells of the and a exosomes or to for and cell to the for After the cells to and the and cell and for from as the and as and the into and into cell cells or and for and into in a to expression cells in a of and the for a to the by an and by expression of and to or in of protein by and to and from Cell p53 and from Cell A for the in study are as treatment by by for IntroductionSkin, an effective barrier that prevents body dehydration and external microorganism penetration, is extremely vulnerable to different types of lesions, such as burns, ulcers, and wounds. Stem cell-based skin tissue engineering has shown great promise for wound healing.1Nourian Dehkordi A. Mirahmadi Babaheydari F. Chehelgerdi M. Raeisi Dehkordi S. Skin tissue engineering: wound healing based on stem-cell-based therapeutic strategies.Stem Cell Res. Ther. 2019; 10: 111Crossref PubMed Scopus (147) Google Scholar, 2Petrof G. Abdul-Wahab A. McGrath J.A. Cell therapy in dermatology.Cold Spring Harb. Perspect. Med. 2014; 4: a015156Crossref PubMed Scopus (19) Google Scholar, 3Sun B.K. Siprashvili Z. Khavari P.A. Advances in skin grafting and treatment of cutaneous wounds.Science. 2014; 346: 941-945Crossref PubMed Scopus (393) Google Scholar Mesenchymal stem cells (MSCs) exist in many adult tissues, such as the bone marrow, adipose tissue, and umbilical cords (UCs).4Pereira R.F. Barrias C.C. Granja P.L. Bartolo P.J. Advanced biofabrication strategies for skin regeneration and repair.Nanomedicine (Lond.). 2013; 8: 603-621Crossref PubMed Scopus (207) Google Scholar Among the types of MSCs, umbilical cord MSCs (ucMSCs) are advantageous because their collection causes no risk or discomfort to the donor, and they have a highly similar gene expression pattern to that of skin fibroblasts;5Schneider R.K. Püllen A. Kramann R. Bornemann J. Knüchel R. Neuss S. Perez-Bouza A. Long-term survival and characterisation of human umbilical cord-derived mesenchymal stem cells on dermal equivalents.Differentiation. 2010; 79: 182-193Crossref PubMed Scopus (54) Google Scholar,6Chen D. Hao H. Tong C. Liu J. Dong L. Ti D. Hou Q. Liu H. Han W. Fu X. Transdifferentiation of Umbilical Cord-Derived Mesenchymal Stem Cells Into Epidermal-Like Cells by the Mimicking Skin Microenvironment.Int. J. Low. Extrem. Wounds. 2015; 14: 136-145Crossref PubMed Scopus (11) Google Scholar thus, ucMSCs have a substantial potential in skin wound repair or tissue engineering. However, the clinical application of ucMSCs still faces several problems, such as the low cell viability of transplanted cells and the risk of immune responses in recipients.7Kurtz A. Mesenchymal stem cell delivery routes and fate.Int. J. Stem Cells. 2008; 1: 1-7Crossref PubMed Scopus (177) Google ScholarExosomes (Exos) derived from MSCs exhibit similar functions to MSCs, but have their own of such as their and X. F. L. L. G. J. J. Hypoxic exosomal of cells via 2019; PubMed Scopus Google H. G. of to for 2019; PubMed Scopus Google Scholar are and R. and of PubMed Scopus Google 2019; PubMed Scopus Google Scholar and to or cells, exosomes an in communication and R. and of PubMed Scopus Google 2019; PubMed Scopus Google Scholar of exosomes is an to tissue repair and M. M. C. Mesenchymal Stem Cell by Google Scholar, J. S. C. M. of for 14: PubMed Scopus Google Scholar, G. R. P.A. S. the of PubMed Scopus Google Scholar However, the of exosomes to the cells from which they are derived and is by and such as or or M. M. A. microenvironment by cells after PubMed Scopus Google Scholar, R. A. M. W. in for in PubMed Scopus Google Scholar, M. W. A. R. H. J. H. H. X. Hou H. X. Hypoxic exosomes tumor and PubMed Scopus Google Scholar skin a of hypoxia exosomes by ucMSCs under hypoxic conditions are different from under normoxic the of types of and S. C. C. C. H. X. M. Cord-Derived Mesenchymal Stem by the Cells Med. PubMed Scopus Google J. J. H. from human umbilical cord accelerate cutaneous wound healing of and 8: PubMed Scopus Google Scholar However, hypoxic ucMSC-derived exosomes have a function in skin wound healing to be cells a in skin repair. hypoxic in enhances the proliferation and of endothelial cells to J. G. and in PubMed Scopus Google and gene therapy for the delivery of to and in wound PubMed Scopus Google Scholar We ucMSCs and endothelial cells in a three-dimensional to skin We that three-dimensional coculture of the types of cells the gene expression of and in and host integration in of ucMSCs or endothelial cells that communication be to and tissue X. J. G. X. of mesenchymal stem cells and endothelial cells enhances host tissue integration and in skin PubMed Scopus Google Scholar that a hypoxic for cells, we that the communication between ucMSCs and endothelial cells under hypoxic conditions be a for skin we that hypoxia the paracrine effect of ucMSCs on endothelial cell proliferation and in and the of ucMSCs on endothelial cells by exosomes. Mechanistically, miR-125b in hypoxic exosomes a that the survival and of endothelial Our study that signaling is for the communication of ucMSCs and endothelial cells, which a therapeutic for skin tissue engineering.

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