Periostin attenuates senescence of human placental mesenchymal stem cells and enhances diabetic wound healing in rats

Refractory diabetic wounds are still big trouble for patients with diabetes, causing great mental and economic burdens. The application of mesenchymal stem cells (MSCs) represents a promising therapeutic strategy, but replicative senescence during ex vivo expansion limits MSC self-renewal and efficacy. Human placental MSCs (plaMSCs) are an attractive allogeneic source, but the mechanisms that maintain their stemness remain unclear. Periostin (POSTN) is a matricellular extracellular matrix protein implicated in skin structure and wound repair, but its role in regulating plaMSC homeostasis and diabetic wound healing is unknown. POSTN expression was compared between early and late passage plaMSCs. Modulation of POSTN expression was achieved via loss- and gain-of-function approaches. Senescence-associated phenotypes, proliferative capacity, cell-cycle distribution, stemness-related factors, multilineage differentiation, and AKT signaling were assessed. The therapeutic effects of POSTN -overexpressing plaMSCs were further evaluated in a streptozotocin-induced diabetic rat full-thickness wound model. Data were presented as mean ± standard deviation (SD) and analyzed using two-tailed Student’s t-tests, with P < 0.05 considered statistically significant. POSTN expression was reduced in late-passage plaMSCs. POSTN knockdown elicited a spectrum of senescence-associated phenotypes, including elevated SA-β-gal activity, upregulated p16 and p21, reduced proliferation, decreased S-phase entry, downregulated stemness-associated markers, impaired osteogenic and chondrogenic differentiation, and suppressed AKT signaling. In contrast, POSTN overexpression alleviated these changes, preserved stemness-related marker expression and differentiation potential, and increased AKT activation. In diabetic rats, all plaMSC-treated groups showed improved wound healing compared with PBS controls, while POSTN -overexpressing plaMSCs produced the greatest enhancement in wound contraction and closure without evident increases in fibrosis. POSTN may function as a regulator of senescence-associated phenotypes and stemness in plaMSCs, potentially in association with AKT signaling. Moreover, POSTN overexpression enhances the therapeutic potential of plaMSCs in diabetic wound repair, supporting its possible application in optimizing placental MSC-based therapy for chronic diabetic wounds.