Mechanical Stimulation Activates Postn-Mediated Wnt/β-catenin Pathway to Enhance BMSCs Paracrine Function and Promote Wound Healing in Diabetic Rats

Background Diabetic wounds exhibit impaired healing due to angiogenic deficiency and dysregulated extracellular matrix homeostasis. Although bone marrow mesenchymal stem cells (BMSCs) promote wound repair through paracrine signaling, their therapeutic efficacy is compromised in diabetic microenvironments. Crucially, emerging evidence implicates Periostin (Postn) as a mechanoresponsive matricellular protein that directly activates Wnt/β-catenin signaling - a pathway governing stem cell paracrine function and tissue regeneration. However, whether mechanical stimulation leverages this Postn-Wnt/β-catenin axis to optimize BMSCs secretory capacity remains unexplored. This study specifically interrogates this mechanotransduction mechanism to develop enhanced therapies for diabetic wounds. Methods BMSCs underwent cyclic stretching (15% strain, 0.5 Hz, 10 h), and paracrine factors (VEGF/TGF-β/bFGF) and pathway proteins were assessed via qRT-PCR, Western blot, and ELISA. Then, Postn knockdown (siRNA) or Wnt/β-catenin inhibition (XAV-939) was implemented to the stretched BMSCs, and paracrine factors were assessed again. Conditioned medium (CM) of stretched BMSCs functionality was evaluated using scratch assay and tube formation assays with Rat umbilical vein endothelial cells (RUVECs) and fibroblasts (Fbs). Finally, a full-thickness diabetic rat wound model was established to validate in vivo efficacy of the CM through wound closure rate, histochemistry, and immunofluorescence. Results Mechanical stimulation significantly increased Postn expression and Wnt/β-catenin signaling, boosting the secretion of VEGF, TGF-β1, and bFGF. Postn knockdown or Wnt/β-catenin pathway inhibition attenuated these effects, while exogenous Postn partially restored function. CM from stretched BMSCs promoted endothelial migration, tube formation, fibroblast migration in vitro, and accelerated wound healing, angiogenesis, and collagen deposition in vivo . Conclusion Mechanical stretch enhances BMSCs’ paracrine function through a Postn-Wnt/β-catenin axis, offering a mechanobiology-based, cell-free approach to improve diabetic wound repair.