不同胚层起源骨髓间充质干细胞的外泌体通过miR-181a-5p调控Hoxa11影响跨胚层游离骨移植的机制研究

游离骨移植是目前治疗颌骨大面积缺损的主要治疗方法，但游离自体颌骨和四肢骨移植修复颌骨缺损存在愈合差异。研究发现，游离四肢骨移植至颌骨缺损后发生软骨化成骨是骨移植愈合延迟的重要原因，其机制尚不清楚。在申请人前期研究基础上，我们推测受植床内颌骨BMSCs可通过外泌体调控四肢骨块内BMSCs的成软骨分化，进而影响跨胚层游离骨移植愈合。为此，本研究首次解析颌骨BMSCs如何通过外泌体递送miR-181a-5p，调控股骨BMSCs的Hoxa11表达及其成骨、成软骨分化；探索颌骨受植床是否通过降低股骨块Hoxa11表达抑制软骨形成；利用慢病毒、miRNA海绵和基因敲入/敲除小鼠，揭示miR-181a-5p调控BMSCs分化影响骨移植愈合机制。该研究为骨移植愈合机制拓展全新的研究视角和理论基础，初步阐明Hoxa11及miR-181a-5p影响跨胚层游离骨移植的作用机制，为加速骨移植愈合提供新的思路。

Free bone grafting is currently the main treatment method for large-scale jaw defects, but there are differences in healing process between free autologous jaw bone and limb bone grafts. In jaw defect, endochondral ossification in free femur graft is considered one of the important causes of delayed union, but the mechanism remains unclear. Based on previous research, we speculate that bone marrow mesenchymal stem cells (BMSCs) in jaw defect area could regulate the chondrogenic differentiation of BMSCs in limb graft through exosomes, and affect bone graft healing. In this study, we analyze how jaw BMSCs regulate chondrogenic differentiation of femoral BMSCs and Hoxa11 through miR-181a-5p-loaded exosomes. We also explore whether the endochondral ossification in free femur graft could be partly inhibited through reducing Hoxa11 expression. Using lentivirus, miRNA sponge and knock-in / knock-out gene mice, we explore the mechanism of miR-181a-5p in regulating differentiation of BMSCs. This study will expand a new perspective and theoretical basis for bone graft healing, and preliminarily clarifies the role of Hoxa11 and miR-181a-5p in bone graft healing. Moreover, this study will provide a new idea and research direction for accelerating the bone graft healing.