Tannic acid-derived nanocarbon promotes angiogenesis by restoring the paracrine activity of senescent BMSCs through the Lama2/integrin α3β1/PI3K/AKT axis.

Abstract

Impaired angiogenesis is a major cause of delayed healing in age-related bone defects, and dysfunction of the pro-angiogenic paracrine activity of senescent bone marrow mesenchymal stem cells (BMSCs) contributes substantially to this vascular deficiency. Here, we synthesised a tannic acid-derived nanocarbon (TANC) and investigated whether it could promote angiogenesis by restoring the pro-angiogenic paracrine function of senescent BMSCs. In an aged rat calvarial defect model treated with locally implanted TANC-loaded GelMA hydrogels, TANC significantly increased blood perfusion, CD31-positive vessel density, and VEGF expression. In vitro, conditioned medium from TANC-treated senescent BMSCs markedly enhanced endothelial proliferation, migration, tube formation, and angiogenesis-related marker expression, whereas direct TANC treatment showed little effect. Transcriptomic screening and functional validation identified Lama2 as a key paracrine mediator regulated by TANC. Lama2 knockdown in vitro and Lama2 neutralisation in vivo both markedly attenuated the pro-angiogenic effect. Mechanistically, Lama2 preferentially interacted with integrin α3β1 on endothelial cells and activated downstream PI3K/AKT signalling. Collectively, these findings show that TANC restores the pro-angiogenic paracrine function of senescent BMSCs through the Lama2/integrin α3β1/PI3K/AKT axis and represents a promising biomaterial-based strategy for age-related bone defects with impaired vascularisation.