Transplantation of Wharton's jelly mesenchymal stem cells encapsulated with Hydroactive® Gel promotes diabetic wound antifibrotic healing in type 2 diabetic rats

Abstract

Diabetic cutaneous ulcers (DCU) are a complication for diabetes patients, mostly occurring in the foot and causing non-healing diabetic foot ulcers. Mesenchymal stem cell (MSC)-based therapy is currently being investigated as a therapeutic avenue for chronic diabetic ulcers. However, poor engraftment, short retention, and low survival still limit the treatment effectiveness. Hydroactive® Gel is a sterile transparent gel made of natural hydrocolloid, which has been widely used for wound management. Whether transplantation of Wharton's jelly mesenchymal stem cells (WJMSCs) encapsulated with Hydroactive® Gel is helpful to diabetic ulcers wound healing remains to be explored. The biocompatibility experiments showed that WJMSCs embedded in Hydroactive® Gel did not influence the cell viability, survival, proliferation, and apoptosis of WJMSCs in vitro. RNA-seq results also implied that Hydroactive® Gel + WJMSCs transplantation activated the “cytokine–cytokine receptor interaction”, “mononuclear cell differentiation”, “regulation of cell–cell adhesion”, and “chemokine receptor activity” to accelerate the inflammatory reaction and epidermis regeneration in diabetic wounds. Histological analysis results demonstrated that Hydroactive® Gel encapsulated WJMSCs transplantation promoted diabetic wound healing and regeneration, indicating improved dermis regeneration, sebaceous gland formation, and type III collagen fiber deposition. Besides, immunohistochemical analysis results showed that Hydroactive® Gel + WJMSCs transplantation also facilitated the transformation of pro-inflammatory M1 macrophages to anti-inflammatory M2 macrophages, cell proliferation, and neovascularization at the wound site. Hydroactive® Gel encapsulation further prolonged the retention time of WJMSCs at the diabetic wound site. Above all, Hydroactive® Gel accelerates WJMSCs-mediated diabetic wound healing by promoting macrophage transformation, facilitating cell proliferation and angiogenesis, and prolonging cell retention time. Our findings may potentially provide a useful therapeutic strategy based on the combination of WJMSCs and biomedical materials for patients with diabetic cutaneous ulcers.