Tissue Sheet Engineered Using Human Umbilical Cord-Derived Mesenchymal Stem Cells Improves Diabetic Wound Healing

Abstract

Diabetic foot ulceration is a common chronic diabetic complication. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been widely used in regenerative medicine owing to their multipotency and easy availability. We developed poly(lactic-co-glycolic acid) (PLGA)-based scaffold to create hUC-MSC tissue sheets. In vitro immunostaining showed that hUC-MSC tissue sheets formed thick and solid tissue sheets with an abundance of extracellular matrix (ECM). Diabetic wounds in mice treated with or without either the hUC-MSC tissue sheet, hUC-MSC injection, or fiber only revealed that hUC-MSC tissue sheet transplantation promoted diabetic wound healing with improved re-epithelialization, collagen deposition, blood vessel formation and maturation, and alleviated inflammation compared to that observed in other groups. Taken collectively, our findings suggest that hUC-MSCs cultured on PLGA scaffolds improve diabetic wound healing, collagen deposition, and angiogenesis, and provide a novel and effective method for cell transplantation, and a promising alternative for diabetic skin wound treatment.

Development of composite functional tissue sheets using hiPSC-CMs and hADSCs to improve the cardiac function after myocardial infarction

“…Numerous studies have highlighted the ability of iPSC-CMs to engraft, establish a functional myocardium, and further improve the cardiac function in diverse animal models of MI [ 22 , 32 ]. PLGA is a biodegradable and biocompatible copolymer that has been used in FDA-approved therapeutic devices including several in our previous studies [ 16 , 18 , 19 , 24 , 25 , 33 ]. Our previous studies have demonstrated that constructing and organizing hiPSC-CMs into tissue sheets using PLGA fiber scaffold in vitro could enhance their therapeutic capabilities after transplantation [ 17 , 19 , 34 ].…”

“…To quantify the density of neovessels and arterioles in the graft and the MI border zone of host, von Willebrand Factor (vWF) and alpha-smooth muscle actin (α-SMA) were used to stain the endothelial cells and vascular smooth muscle cells, respectively, while cell nuclei were counterstained blue for DAPI. The neovessels were represented by orange staining, and orange/green double staining represented arterioles, as previously reported [ 25 ]. Images were captured using a confocal microscope (Nikon A1, Nikon, New York, NY, USA) and analyzed with ImageJ software (NIH, Bethesda, MD, USA).…”

“…Next, hADSCs were obtained from PromoCell (C-12977, PromoCell, Heidelberg, Germany). The hADSCs were cultured and expanded as previously described [ 25 ]. Briefly, cryopreserved passage 2 (P2) cells were obtained and cultured in the mesenchymal stem cell (MSC) Xeno-Free culture medium (Takara Bio Inc., Shiga, Japan) at 37 °C in a 5% CO 2 incubator.…”

“…Its clinical use in humans has been approved by the U.S. Food and Drug Administration (FDA) [ 23 , 24 ]. In our previous studies, we have constructed 3D hiPSC-CM tissue sheets and 3D MSC tissue sheets using PLGA fiber scaffold [ 17 , 25 ]. Our tissue sheet technology based on PLGA fiber scaffold exhibits numerous advantages, including well-organized and thick tissue, abundant ECM deposition, enhanced secretion, simple construction methods, excellent operability, and ultimately contributes to MI therapy [ 13 , [16] , [17] , [18] , [19] , [20] , 25 ].…”

“…In our previous studies, we have constructed 3D hiPSC-CM tissue sheets and 3D MSC tissue sheets using PLGA fiber scaffold [ 17 , 25 ]. Our tissue sheet technology based on PLGA fiber scaffold exhibits numerous advantages, including well-organized and thick tissue, abundant ECM deposition, enhanced secretion, simple construction methods, excellent operability, and ultimately contributes to MI therapy [ 13 , [16] , [17] , [18] , [19] , [20] , 25 ]. In addition, previous studies have demonstrated that MSCs can reduce the apoptosis, improve the maturation, and inhibit the immune rejection of CM [ [26] , [27] , [28] ].…”