dCas9-Based PDGFR–β Activation ADSCs Accelerate Wound Healing in Diabetic Mice through Angiogenesis and ECM Remodeling

Abstract

The chronic wound represents a serious disease characterized by a failure to heal damaged skin and surrounding soft tissue. Mesenchymal stem cells (MSCs) derived from adipose tissue (ADSCs) are a promising therapeutic strategy, but their heterogeneity may result in varying or insufficient therapeutic capabilities. In this study, we discovered that all ADSCs populations expressed platelet–derived growth factor receptor β (PDGFR–β), while the expression level decreased dynamically with passages. Thus, using a CRISPRa–based system, we endogenously overexpressed PDGFR–β in ADSCs. Moreover, a series of in vivo and in vitro experiments were conducted to determine the functional changes in PDGFR–β activation ADSCs (AC–ADSCs) and to investigate the underlying mechanisms. With the activation of PDGFR–β, AC–ADSCs exhibited enhanced migration, survival, and paracrine capacity relative to control ADSCs (CON–ADSCs). In addition, the secretion components of AC–ADSCs contained more pro–angiogenic factors and extracellular matrix–associated molecules, which promoted the function of endothelial cells (ECs) in vitro. Additionally, in in vivo transplantation experiments, the AC–ADSCs transplantation group demonstrated improved wound healing rates, stronger collagen deposition, and angiogenesis. Consequently, our findings revealed that PDGFR–β overexpression enhanced the migration, survival, and paracrine capacity of ADSCs and improved therapeutic effects after transplantation to diabetic mice.