Apelin-13 enhances BMSCs osteogenic differentiation and bone regeneration under hypoxia via upregulation of Ibsp

BACKGROUND: Apelin-13 plays a critical role in promoting angiogenesis and regulating cellular metabolism. However, the short half-life of Apelin-13 in vivo limits its further applications. Stem cell transplantation has been widely applied in tissue regeneration, but the low survival rate of transplanted stem cells in vivo restricts its therapeutic efficacy. This study aims to combine Apelin-13 with stem cell transplantation to enhance the survival rate of transplanted stem cells and promote bone regeneration. METHODS: In this study, BMSCs and HUVEC were pretreated with different concentrations of Apelin-13 to investigate its effects on their proliferation, differentiation capacities under hypoxic conditions (1% O₂). A rat mandibular bone defect model was employed to evaluate the promotive effects of Apelin-13-BMSCs and Apelin-13-HUVEC transplantation on bone regeneration, and RNA sequencing together with a rat closed femoral fracture model was further used to explore the potential mechanisms by which Apelin-13 enhances BMSC proliferation and differentiation. RESULTS: Apelin-13 enhances the proliferative and differentiation capacities of BMSCs and HUVEC under hypoxic conditions, reduces apoptosis, and exerts these promotive effects in a dose-dependent manner. BMSCs pretreated with Apelin-13 markedly facilitate the repair of rat mandibular bone defects and the healing of femoral fractures. Mechanistically, Apelin-13 promotes proliferation and osteogenic differentiation by upregulating Ibsp expression in BMSCs. CONCLUSION: BMSCs pretreated with Apelin-13 exhibited favorable regenerative and differentiation capacities in both in vitro and in vivo experiments, providing a potential strategy to address the challenges of low survival rates and stemness decline following stem cell transplantation in vivo.