HGF/c-Met调控间充质干细胞归巢对急性肾损伤大鼠肾功能的保护作用和机制研究

Acute kidney injury is characterized by a rapidly declining renal function. Over the decade, progress in the pathophysiology of AKI has not translated into successful pharmacological intervention. However, the efficacy of therapeutic applications is largely decided by the homing and migration of MSCs to the sites of tissue damage. Emerging evidence suggests that only a very small percentage of MSCs following systemic delivery ultimately reach the target tissue. Hence, improving the homing capacity of MSCs is vital important for treatment of AKI. The HGF/c-Met signaling pathway is believed to participate in diverse biological processes such as cellular proliferation and apoptosis. C-met is well established as the receptor of HGF and belongs to the transmembrane tyrosine kinase family. Particularly, a number of studies have demonstrated that HGF can accelerate cell migration by binding its receptor c-Met. Strategy using c-met modification to upregulate its functional expression may be helpful for enhancing the homing efficiency of MSCs to the damaged kidney sites. In addition, our previous study shown that the level of HGF significantly upregulated after renal injury induced by IR injury. Thus, we speculated that c-met modification could enhance MSCs homing to the rat kidney following ischemia-reperfusion. In the present study, we firstly construct c-met-MSCs by overexpression of c-met, and subsequently explored whether c-met-MSCs transplantation confers an incremental renoprotective effect in IR-induced AKI. Our study may glean a better understanding of MSCs-mediated repair of the kidney and lead to new strategy for treatment of AKI.

急性肾损伤(AKI)的主要特征为肾功能快速恶化，间充质干细胞(MSC)移植为AKI组织修复提供了极具希望的治疗途径，但MSC向损伤组织归巢率低限制了其疗效。肝细胞生长因子（HGF）及其受体c-Met在调控MSC归巢至损伤组织的过程中发挥着关键作用。我们前期研究发现，AKI大鼠早期肾损伤组织中HGF水平显著增高，Transwell迁移实验显示HGF能够显著诱导MSC跨膜迁移，因而推测高表达c-Met能够促进MSC归巢至损伤肾组织。本研究拟通过构建c-Met高表达的MSC和缺血性急性肾损伤大鼠模型，①观察高表达c-Met的MSC，在肾损伤组织释放的HGF介导下，能否更有效地归巢至损伤组织；②观察FAK及其下游信号分子ERK1/2在HGF/c-Met调控MSC迁移中的作用，以阐明HGF/c-Met调控MSC归巢至损伤肾组织的具体分子机制，为增强MSC疗效开辟新的途径。

急性肾损伤(AKI)的主要特征为肾功能快速恶化，间充质干细胞(MSC)移植为AKI组织修复提供了极具希望的治疗途径，但MSC向损伤组织归巢率低限制了其疗效。肝细胞生长因子（HGF）及其受体c-Met在调控MSC归巢至损伤组织的过程中发挥着关键作用。本研究拟①构建含c-Met的质粒，慢病毒转染使MSC高表达c-Met, 观察HGF对高表达c-Met的MSC向损伤肾组织归巢的情况，证实HGF/c-Met在调控MSC向损伤肾组织归巢中的重要作用；②干预MSC表面粘附蛋白FAK及其下游ERK1/2信号通路，证实其在HGF/c-Met调控MSC归巢中的重要作用。本研究将为优化MSC治疗AKI提供理论依据和新的思路。..本文的主要结论是：.1．AKI大鼠早期肾损伤组织中HGF水平显著增高，Transwell迁移实验显示HGF能够显著诱导MSC跨膜迁移。.2．高表达c-Met的MSC细胞，在肾损伤组织释放的HGF介导下，能够更有效地归巢至损伤肾组织，进一步减轻了缺血再灌注所致的肾损伤程度。.3．其作用机制一方面通过HGF对高表达c-Met的MSC的趋化作用。另一方面是在HGF/c-Met调控MSC归巢过程中，FAK及其下游的ERK1/2信号通路发挥着重要的调节作用。