大鼠椎间盘内源性修复机制的研究：基于HGF/c-met信号轴介导的椎间盘巢源性干细胞自体内迁移

Exogenous stem cells transplantation is thought to be an effective approach on the treatment of intervertebral disc degeneration (IVDD), but with some unavoidable defects that need to be improved. While endogenous repair process may be a desirable way to solve the problems. The finding of stem cell niches in the disc region and the migration characteristics of the stem cells from the niches (ISN-SCs) provided us new horizons on the endogenous repair of IVDD. Our previous study had successfully separated, cultured and characterized the ISN-SCs from rats. While little is known about the migration mechanisms and the migration- to- repair effects. In light of that HGF/c-met signal axis plays critical chemotaxis effect in the processes of tumor invasion and stem cells migration, and that our preliminary experiments proved HGF expressed on the nucleus pulposus and HGF mediated the migration process of ISN-SCs, we intend to chose HGF/c-met signal axis as the key point of the study to illustrate the mechanisms of ISN-SCs migration. Besides, the repair effects of ISN-SCs on IVDD are need to be clarified in vivo and vitro. Finally, the expression and exocrine secretion levels of HGF in the degenerated discs with varying degrees will be examined to analyze the potential effects of IVDD degrees on the ISN-SCs migration- to- repair effect. Illustration of these key issues will be helpful to know further about the endogenous repair process of the discs based on ISN-SCs migration, to provide more sufficient theoretical basis for endogenous repair of IVDD, and to seek for new therapeutic targets to promote the migration- to- repair effect.

椎间盘干细胞巢的发现及其巢源性干细胞（ISN-SCs）迁移理论的提出，为椎间盘退变（IVDD）的内源性干细胞修复打开了新的思路。我们的前期研究成功地对ISN-SCs进行了体外分离、培养和特性鉴定，然而尚缺乏其迁移机制及迁移致修复效应的研究。鉴于HGF/c-met信号轴在肿瘤侵袭和干细胞迁移过程中的介导作用，以及预实验中HGF在髓核细胞的表达及其介导的ISN-SCs迁移现象，我们拟将HGF/c-met信号轴作为研究切入点，以期阐明其介导的ISN-SCs迁移机制；同时明确ISN-SCs对IVDD的修复作用；通过检测不同程度IVDD状态下HGF的表达和外分泌差异，分析IVDD程度对ISN-SCs自体内迁移致内源性修复效应的潜在影响。阐明这些问题必将有助于我们深入认识基于ISN-SCs迁移的椎间盘内源性修复过程，为IVDD的内源性修复提供充分的理论基础，从而寻找新的治疗靶点促进其迁移致修复效应。

椎间盘干细胞巢的发现及其巢源性干细胞(ISN-SCs)迁移理论的提出,为椎间盘退变(I VDD)的内源性干细胞修复打开了新的思路。我们的前期研究成功地对ISN-SCs进行了体外分离 、培养和特性鉴定,然而尚缺乏其迁移机制及迁移致修复效应的研究。该研究将HGF/c-met信号轴作为研究切入点,阐明了其介导的ISN-SCs迁移机制;同时明确了ISN-SCs对IVDD的修复作用;通过检测不同程度IVDD状态下HGF的表达差异,分析IVDD程度对ISN-SCs自体内迁移致内源性修复效应的潜在影响。研究结果表明：（1）ISN-SCs迁移可由HGF/c-met信号轴介导，其通过激活胞内PI3K/AKT信号通路，进而调节F-actin的形成和重组，促进其迁移过程；（2）ISN-SCs对衰老髓核细胞及椎间盘退变具有良好修复效应和较好的应用潜能；（3）HGF可诱导ISN-SCs向椎间盘内部迁移，从而潜在激发着该内源性修复过程；（4）退变的椎间盘组织中HGF表达进一步减少，可能一定程度上会减弱椎间盘自身内源性促ISN-SCs迁移致修复过程，从而形成椎间盘退变的恶性循环。该研究有助于我们深入认识基于ISN-SCs迁移的椎间盘内源性修复过程,为IVDD的内源性修复研究提供充分的理论基础。