PDLSCs-ApoEVs enhance bone regeneration through MAPK1/3-induced STC1 upregulation in endothelial cells via the FOS pathway

Abstract

Effective repair of severe bone defects is a significant challenge in clinical practice. Recent research has highlighted the potential of apoptotic vesicles derived from mesenchymal stem cells (MSC-ApoEVs) for tissue repair. This study specifically explored the use of ApoEVs derived from periodontal ligament stem cells (PDLSCs-ApoEVs) and their ability to treat localized bone defects. In a mouse model with cranial defects, PDLSCs-ApoEVs were found to stimulate bone regeneration effectively. However, in vitro studies showed that these vesicles had limited ability to promote osteogenic differentiation in bone marrow stromal cells (BMSCs). Further investigation revealed that PDLSCs-ApoEVs enhanced angiogenesis and osteogenesis by coupling these two processes. The mechanism involved is MAPK1/3 within PDLSCs-ApoEVs, which increased the expression of STC1 in endothelial cells through the MAPK1/3-FOS pathway. STC1, a secretory protein, promoted both angiogenesis and osteogenic differentiation, forming H-type blood vessels in the bone-forming environment. This combined effect of angiogenesis and osteogenesis significantly improved bone repair in the mouse model. Overall, this study sheds light on the role and mechanisms of PDLSCs-ApoEVs in bone formation, offering new perspectives on their potential for tissue regeneration therapy.