神经嵴源性间充质干细胞在下颌骨牵张成骨中的成骨分化特点及其机理研究

It remains largely unknown on the mechanisms of osteogenic differentiation in mesenchymal stem cells (MSC) during jaw bone distraction osteogenesis (DO) and its efficiency awaits improvement . We have demonstrated in this project that sympathetic nerve-endothelial cell complex regulates MSC mobilization in DO, and found that osteogenic differentiation capability differs between jaw bone MSC and long bone MSC undergoing distraction. From developmental point of view, jaw bones are mainly from neural crest whereas long bones are from mesoderm. Therefore, it is important to determine the characteristics of osteogenic differentiation in MSC from different developmental origins, in order to improve the osteogenic efficiency of DO. In this proposal, we will perform mandibular and femur DO in Wnt1-Cre; R26R transgenic mice with neural crest labeling, and determine the contribution of neural crest-derived MSC in jaw bone DO by neural crest cell tracking and bone morphological studies; determine the characteristics of osteogenic differentiation of neural crest-derived MSC undergoing distraction; detect tension-osteogenesis pathways such as p38MAPK, and determine their roles in distraction-induced osteogenic differentiation of neural crest-derived MSC. Finally, we will apply activators of the related pathways such as p38MAPK in the mouse model of mandibular DO, and determine their effects to enhance osteogenic differentiation of neural crest-derived MSC, thereby contributing to the improvement of osteogenic efficiency in jaw bone DO.

颌骨牵张成骨(DO)的间充质干细胞（MSC）成骨分化机理不明，成骨效率有待提高。本课题已经证明交感神经/内皮细胞复合体调控牵张力下的MSC动员，并发现牵张力下长骨MSC的成骨分化能力不同于颌骨MSC。颌骨的主要发育来源是神经嵴，而长骨来源于中胚层。因此，明确不同发育来源MSC的成骨分化特点及其机理，有利于改善DO的成骨效率。本研究拟采用神经嵴标记的Wnt1-Cre; R26R转基因小鼠，建立下颌骨和股骨DO模型，通过神经嵴源性细胞追踪和骨形态学分析，明确神经嵴源性MSC在下颌骨DO的作用；通过体内、外牵张力刺激神经嵴源性MSC，明确其成骨分化的特点；检测p38MAPK等张力性成骨相关通路的表达，探讨其在神经嵴源性MSC的张力性成骨分化的功能。最后，在小鼠下颌骨DO中应用p38MAPK等相关通路的激动剂，研究其促进神经嵴源性MSC成骨分化的效果，为提高颌骨DO的成骨效率提供实验依据。

颌骨牵张成骨(DO)的间充质干细胞（MSC）成骨分化机理不明，成骨效率有待提高。本课题在前一项青年基金已证明交感神经/内皮细胞复合体调控牵张力下的MSC 动员的基础上，明确了颌骨神经嵴来源MSC在张应力下的的成骨分化特点及其机理。具体地，我们采用神经嵴标记小鼠，明确了下颌骨神经嵴源性MSC在牵张应力作用下动员到成骨前线的决定性作用。通过体内、外牵张力刺激颌骨神经嵴源性MSC，明确了其成骨分化的特点，并初步明确了p38等张力性成骨相关通路在其迁移和成骨分化中的重要作用。最后通过应用p38激动剂或药物调控神经系统，发现了其促进神经嵴源性MSC迁移和成骨分化的效果，为提高颌骨DO的成骨效率提供实验依据。本课题资助下共发表SCI收录论著10篇（含2篇已接收）。