Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China.
Int J Mol Sci. 2023 Mar 21;24(6):5949. doi: 10.3390/ijms24065949.
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.
慢性创面是一种严重的疾病，其特征是皮肤和周围软组织损伤后无法愈合。脂肪来源的间充质干细胞（ADSCs）是一种很有前途的治疗策略，但它们的异质性可能导致治疗能力的差异或不足。在本研究中，我们发现所有 ADSC 群体都表达血小板衍生生长因子受体β（PDGFR-β），而其表达水平随传代而动态下降。因此，我们使用基于 CRISPRa 的系统，在 ADSC 中内源性过表达 PDGFR-β。此外，进行了一系列体内和体外实验，以确定 PDGFR-β 激活 ADSC（AC-ADSC）的功能变化，并探讨其潜在机制。随着 PDGFR-β 的激活，AC-ADSC 的迁移、存活和旁分泌能力相对于对照 ADSC（CON-ADSC）增强。此外，AC-ADSC 的分泌成分含有更多的促血管生成因子和细胞外基质相关分子，促进了体外内皮细胞（EC）的功能。此外，在体内移植实验中，AC-ADSC 移植组表现出更高的创面愈合率、更强的胶原沉积和血管生成。因此，我们的研究结果表明，PDGFR-β 的过表达增强了 ADSC 的迁移、存活和旁分泌能力，并改善了糖尿病小鼠移植后的治疗效果。
