Piezo1-activated mesenchymal stem cells-derived extracellular matrix hydrogel promotes the repair of osteoporotic bone defects through osteogenic and angiogenic coupling

Abstract Osteoporotic bone defects present a significant clinical challenge due to impaired osteogenesis and angiogenesis, often leading to poor healing and bone regeneration. Current therapeutic approaches, including demineralized cancellous bone matrix and synthetic bioactive materials, are often limited by issues such as inadequate donor sources and immune responses. In this study, we developed a novel extracellular matrix hydrogel by optimizing extracellular matrix (ECM) derived from mesenchymal stem cells (MSCs) through preconditioning with Yoda1 (Y-ECM-gel), the Piezo1 mechanosensory channel agonist. The Y-ECM-gel retains the diversity of bioactive factors and structural features found in natural ECM while exhibiting remarkable physical stability. Our in vitro experiments demonstrated that Y-ECM-gel significantly promoted the proliferation, migration, and osteogenic differentiation of mouse preosteoblast cells (MC3T3-E1), enhancing osteogenesis via activation of the PI3K/AKT signaling pathway. Additionally, Y-ECM-gel promoted the proliferation, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs). In vivo experiments, it significantly stimulated bone tissue formation and neovascularization in the osteoporotic bone defect model. These findings indicate that Y-ECM-gel can restore bone homeostasis by promoting osteogenic-angiogenic coupling, providing a promising, minimally invasive, and highly effective therapeutic strategy for bone regeneration in osteoporotic conditions.