AntimiR-34a增强脂肪干细胞对骨形成蛋白高效诱导成骨作用反应性的分子机制研究

项目名称： AntimiR-34a增强脂肪干细胞对骨形成蛋白高效诱导成骨作用反应性的分子机制研究

项目编号： No.81671926

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 医药、卫生

项目作者： 吴慧玲

作者单位： 浙江大学

项目金额： 25万元

中文摘要： 以脂肪干细胞（hASCs）和骨形成蛋白（BMP）为基础的骨组织工程技术是治疗颜面部骨缺损的研究热点之一。同行研究表明：因为供体表观遗传修饰差异极大，hASCs对于BMP的成骨诱导具有反应性低和不确定性。改变hASCs的成脂分化趋势，重置成骨分化通路是提高hASCs对于BMP成骨诱导反应性的关键。我们前期研究发现通过antimiR-34a这一表观遗传修饰可以显著增强hASCs对于BMP成骨诱导关键蛋白的表达，因此具有良好的应用前景。然而，antimiR-34a促进hASCs成骨分化的分子机制未见报道。因此提出假设：antimiR-34a通过上调Notch-TAZ、NF-κB-TAZ通路和直接作用于BMP通路是实现其促进hASCs成骨分化的主要机制。在本研究中，我们拟阐明antimiR-34a促进hASCs成骨分化的信号通路机制，为构建以hASCs和BMP为基础的组织工程化骨提供理论基础。

中文关键词： 骨组织工程；干细胞移植；信号通路；分泌蛋白

英文摘要： The bone tissue engineering technology with adipose derived stem cells (hASC) and bone morphogenetic protein (BMP) is one of the research hot element in the treatment of facial bone defects. Our previous studies indicated that: as the donors’ epigenetic modifications vary greatly, hASCs have a lower response and uncertainty for BMP induction. Changing the hASCs’ differentiation trend into fat, and resetting their osteogenic differentiation pathway is the key to improve hASCs’ osteogenic induction reactivity with BMP. Our previous study found that antimiR-34a through this epigenetic modification can significantly enhance the expression of osteogenic related proteins when hASCs treated with BMP, so the antimiR-34a has a good application prospect. However, the molecular mechanism of antimiR-34a promoting hASC osteogenesis has not been reported. We hypothesized that antimiR-34a upregulates Notch-TAZ, NF-kappaB-TAZ pathway is a major mechanism for antimiR-34a to achieve its osteogenesis. In this study, we proposed by RNA sequencing, CHIP-sequencing, CoIP, RNA silencing, and inhibitors, etc. to elucidate the signal transduction mechanism of antimiR-34a promoting hASC osteogenesis, provide a theoretical basis for the effective construction of tissue engineered bone with hASCs and BMP.

英文关键词： bone tissue engineering;stem cell transplantation;signal pathway;secreted protein