Abstract
BackgroundHuman induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) have emerged as a promising alternative for stem cell transplantation therapy. Exosomes derived from mesenchymal stem cells (MSC-Exos) can play important roles in repairing injured tissues. However, to date, no reports have demonstrated the use of hiPSC-MSC-Exos in cutaneous wound healing, and little is known regarding their underlying mechanisms in tissue repair.MethodshiPSC-MSC-Exos were injected subcutaneously around wound sites in a rat model and the efficacy of hiPSC-MSC-Exos was assessed by measuring wound closure areas, by histological and immunofluorescence examinations. We also evaluated the in vitro effects of hiPSC-MSC-Exos on both the proliferation and migration of human dermal fibroblasts and human umbilical vein endothelial cells (HUVECs) by cell-counting and scratch assays, respectively. The effects of exosomes on fibroblast collagen and elastin secretion were studied in enzyme-linked immunosorbent assays and quantitative reverse-transcriptase–polymerase chain reaction (qRT-PCR). In vitro capillary network formation was determined in tube-formation assays.ResultsTransplanting hiPSC-MSC-Exos to wound sites resulted in accelerated re-epithelialization, reduced scar widths, and the promotion of collagen maturity. Moreover, hiPSC-MSC-Exos not only promoted the generation of newly formed vessels, but also accelerated their maturation in wound sites. We found that hiPSC-MSC-Exos stimulated the proliferation and migration of human dermal fibroblasts and HUVECs in a dose-dependent manner in vitro. Similarly, Type I, III collagen and elastin secretion and mRNA expression by fibroblasts and tube formation by HUVECs were also increased with increasing hiPSC-MSC-Exos concentrations.ConclusionsOur findings suggest that hiPSC-MSC-Exos can facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. These data provide the first evidence for the potential of hiPSC-MSC-Exos in treating cutaneous wounds.
Highlights
The skin is frequently injured by acute and chronic wounds, such as diabetic skin ulcerations or extensive burns, which cause physical and mental suffering in affected individuals, as well as heavy financial burdens at the familial and societal levels
Consistent with our hypothesis, we found that hiPSC-Mesenchymal stem cells (MSCs)-Exos significantly enhanced wound healing, collagen synthesis, and the genesis of newly formed vessels and mature vessels in wound sites
These results suggest that the derived hiPSC-MSCs possessed MSC properties and multipotency
Summary
The skin is frequently injured by acute and chronic wounds, such as diabetic skin ulcerations or extensive burns, which cause physical and mental suffering in affected individuals, as well as heavy financial burdens at the familial and societal levels. The application of ESCs faces substantial ethical and safety hurdles These factors restrict the clinical application of MSCs and ESCs. Induced pluripotent stem cells (iPSCs) are similar to ESCs in terms of morphology, self-renewal, and differentiation capacity [6,7], and iPSCs can be generated from any tissue type in the body. Patient-specific iPSC-MSCs can be used for autologous transplantation without immunological rejection and the beneficial effects of iPSC-MSCs in tissue repair have already been demonstrated [9,12,13] Despite their apparent advantages, issues of allogeneic and xenogeneic immunological rejection and chromosomal variation in cell transplantation therapy still exist [14,15]. To date, no reports have demonstrated the use of hiPSC-MSC-Exos in cutaneous wound healing, and little is known regarding their underlying mechanisms in tissue repair
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