血红素加氧酶1调控BMP9诱导的间充质干细胞成骨/成脂分化

The treatment of bone defects is still a major clinical problem. BMP9 has strong potential to induce osteogenic differentiation of mesenchymal stem cells (MSCs), and brings hope for the MSCs-based bone defect treatment. However, BMP9 can induce both osteogenic differentiation and adipogenic differentiation of MSCs. Therefore, it is particularly important to understand the regulatory mechanism involved in BMP9-induced osteogenic/adipogenic differentiation of MSCs, as well as to identify related key regulatory factors. Our preliminary data showed that Hmox1 can regulate both osteogenic and adipogenic differentiation of MSCs induced by BMP9. Up-regulation of Hmox1 can promote BMP9-induced MSCs osteogenic differentiation whereas inhibit adipogenic differentiation, and vice versa. In this project, we will firstly analysis and characterize the effect of Hmox1 on BMP9-induced osteogenic and adipogenic differentiation of MSCs. Secondly, we will explore the potential therapeutic effect of Hmox1 on BMP9-induced MSCs-based bone defects treatment. Thirdly we will investigate the molecular mechanism through which Hmox1 to regulate BMP9-induced osteogenic and adipogenic differentiation of MSCs. Collectively, this project will enrich our understanding of BMP9-induced osteogenic and adipogenic differentiation of MSCs, and will be hopefully expected to offer a new strategy in the treatment of bone defects.

骨缺损修复是临床一大难题，BMP9具有强效诱导间充质干细胞（Mesenchymal Stem Cells，MSCs)成骨分化的能力，为干细胞生物治疗的骨缺损修复带来希望。但BMP9对MSCs兼具成骨诱导和成脂诱导能力，因此对BMP9诱导MSCs成骨分化和成脂分化过程中调控机制的理解，以及对关键调控因子的鉴定显得尤为重要。课题组前期发现血红素加氧酶（Hmox1）可调控BMP9诱导的MSCs成骨和成脂分化：上调Hmox1可促进BMP9诱导的MSCs成骨分化但抑制成脂，反之亦然。本项目拟在此基础上，系统分析Hmox1对BMP9诱导MSCs成骨及成脂分化的影响及特点；探索利用Hmox1来增强BMP9诱导的MSCs对骨缺损修复的可行性；分析Hmox1调控BMP9诱导MSCs成骨和成脂分化的相关机理。项目的实施将丰富我们对BMP9调控MSCs成骨和成脂分化的认识，同时也为骨缺损治疗提供新思路。

BMP9是一种强效诱导间充质干细胞（MSCs）成骨分化的细胞因子，具有潜在临床应用价值。但课题组前期发现BMP9可以同时诱导间充质干细胞成骨分化和成脂分化。因此，深入分析BMP9诱导间充质干细胞成骨分化和成脂分化过程中的调控机制，并鉴定相关的关键调控因子，对于有效利用BMP9的诱导成骨能力显得尤为重要。本课题主要分析Hmox1对BMP9诱导的间充质干细胞成骨分化和成脂分化的影响，结果发现： BMP9可以上调间充质干细胞中Hmox1的表达。Hmox1对于BMP9诱导的间充质干细胞成骨分化和成骨分化具有重要的调控作用。抑制Hmox1，BMP9诱导的间充质干细胞成骨分化减弱但成脂分化增强。活化Hmox1，BMP9诱导的间充质干细胞成骨分化进一步增强但成脂分化减弱。而Hmox1调控BMP9诱导的间充质干细胞成骨分化和成脂分化的机制包括： 1）影响经典的Smad、p38和ERK1/2信号；2）影响β-catenin信号。更有意义的是，BMP9和Hmox1联合使用，可以获得比单独使用BMP9更好的促进颅骨缺损修复的效果。本课题的完成有助于丰富和完善我们对BMP9诱导间充质干细胞成骨分化和成脂分化的认识，为将来BMP9在以MSCs为种子细胞的骨组织工程的应用，提供更为灵活和有效的思路。