表观修饰重编程的骨髓基质干细胞治疗激素性股骨头坏死的相关研究

The multi-differentiation potential of bone marrow stromal cells is considered to be the key target of the femoral head necrosis of the central link in the pathogenesis and treatment. Bone marrow stromal cells lack homing ability to bone tissue, and avascular necrosis of bone marrow stromal stem cells into bone into the vascular differentiation potential decreased significantly restrict the clinical efficacy of its treatment of osteonecrosis. Recent studies have shown that in vitro long-term culture of MSCs apparent genetic status change, have fallen due to its easy to aging, differentiation potential. Reversal of the MSCs epigenetic change is expected to opened up a new breakthrough in the prevention and control research for avascular necrosis. This study ischemic necrosis of the femoral head model OCt4 genetic reprogramming of bone marrow stromal stem cells, combined with the apparent modification of the small molecule compounds of induction to the differentiation potential of stem cells and improve the bone into the blood vessel function, simultaneous detection of modified reprogramming of bone marrow stromal cell transplantation for treatment of osteonecrosis of the efficacy, depth effect and mechanism of the reprogramming of epigenetic modification of bone marrow stromal cells in the treatment of femoral head necrosis, and to provide new ideas for the early clinical treatment of femoral head necrosis。

多向分化潜能的骨髓基质干细胞被认为是股骨头坏死发病机制的中心环节及治疗的关键靶点。但骨髓基质干细胞缺乏向骨组织的归巢能力，且股骨头缺血坏死的骨髓基质干细胞成骨成血管分化潜能显著下降，制约其治疗骨坏死的临床疗效。而最近研究表明体外长期培养后，MSCs表观遗传状态改变，是其易于衰老，分化潜能降低的主要原因。因此逆转MSCs表观遗传学的改变有望为股骨头缺血性坏死防治研究开辟了新的突破点。本研究拟通过激素性股骨头缺血坏死模型，采用OCt4基因重编程骨髓基质干细胞，结合小分子化合物的表观修饰，以期诱导多向分化潜能干细胞，提高成骨成血管功能，同时检测修饰后重编程的骨髓基质干细胞移植治疗的骨坏死的疗效，从而深入探讨表观修饰重编程的骨髓基质干细胞在股骨头坏死治疗中的作用及其机制，为股骨头坏死的临床早期治疗提供新的思路。

骨髓间充质干细胞的表观遗传学的改变在股骨头缺血性坏死中可能起重要作用。本课题发现股骨头坏死患者股骨头骨髓间充质干细胞Micro-RNA表达存在异常。对一种异常MicroRNA miR-17-5P深入研究发现，miR-17-5P通过作用于SMAD7，从而促进骨髓间充质干细胞RUNX2和Collagen 1A1等成骨基因的表达。股骨头坏死患者miR-17-5P表达显著减低，导致骨髓间充质干细成骨功能受损，是股骨头坏死发病的可能原因。本课题组还发现甲基化抑制剂5’-氮杂胞苷可以促进骨髓间充质干细胞的分化。地塞米松具有抑制骨髓间充质干细胞成骨分化，促进成脂分化的作用。5’-氮杂胞苷可以逆转地塞米松对骨髓间充质干细胞的成脂分化作用，同时促进成骨分化。综上所述，骨髓间充质干细胞的表观遗传学的异常在股骨头缺血性坏死中可能起重要作用。项目资助发表SCI论文3篇，发表核心论文3篇，待发表1篇。培养博士研究生2名，已取得博士学位；培养硕士研究生4名，2名已取得硕士学位，2名在读。项目投入经费70万元，支出68.07万元，各项支出基本与预算相符。剩余经费1.93万元，剩余经费计划用于本项目研究后续支出。