经肾动脉移植SDF-1转染的骨髓 MSCs对鼠慢性肾损伤细胞程序性坏死的影响和机制

Chronic kidney disease (CKD) is a worldwide disease with high morbidity and mortality. In our previous study, we found that transplantion of bone marrow MSCs has a protective role in the CKD. And we have also confirmed that stromal cell derived factor-1 (SDF-1) can promote the migration of MSCs to the injured renal cells. It has been reported that SDF-1 preconditioning is conducive to the survival and proliferation of MSCs. However, it is unclear whether over expression of SDF-1 in CKD could enhance the ability of MSCs to promote the repairment of renal tissues. We hypothesize that by tansplanted into the renal artery， MSCs transfected with SDF-1 might able to attenuate the necroptosis of renal intrinsic cells for renal protection in CKD. In this study, we intend to establish a model of CKD to assese the potential effects of SDF-1 transfected MSCs on the renal intrinsic cells necroptosis and provide evidence for further exploration of the possible MSCs treatments in CKD patients.

慢性肾脏病(chronic kidney disease，CKD)在全球范围内具有高发病率和高致死率。我们前期研究中发现骨髓间充质干细胞（mesenchymal stem cells, MSCs）移植对CKD肾功能有保护作用，且证实基质细胞衍生因子-1(stromal cell derived factor-1，SDF-1)可促进MSCs向受损肾脏细胞迁移。有报道表明SDF-1预处理利于MSCs存活和增殖，但在CKD中SDF-1过表达能否增强MSCs的促肾脏组织修复能力，尚不明确。设想：SDF-1转染的MSCs经肾动脉移植可通过抑制肾脏固有细胞程序性坏死(necroptosis)而对CKD发挥肾脏保护作用。本研究拟建立CKD模型，采用多种实验手段，探讨经SDF-1转染的MSCs对CKD肾固有细胞necroptosis的影响，为进一步探索MSCs治疗CKD的可行性奠定基础。

慢性肾脏病(chronic kidney disease，CKD)在全球范围内具有高发病率和高致死率。研究证实 SDF-1 转染的骨髓 MSCs 通过肾动脉移植更利于 MSCs 归巢至受损伤肾脏并发挥促肾脏修复作用。本项目通过体外实验和体内实验两个部分探索了移植SDF-1转染的骨髓MSCs对慢性肾病肾组织中固有细胞程序性坏死的影响及参与作用的信号通路，并比较经肾动脉途径和外周静脉途径移植骨髓MSCs对肾固有细胞程序性坏死的影响，进一步揭示干细胞移植治疗慢性肾脏病的可能机制。从我们当前的研究中发现，以病毒载体转染SDF-1的方式预处理骨髓MSCs，然后将SDF-1转染的骨髓MSCs分别与被缺血缺氧状态诱导的肾小球系膜细胞及肾小管上皮细胞共同培养，发现SDF-1转染的骨髓MSCs更能有效抑制肾固有细胞（肾小球系膜细胞及肾小管上皮细胞）的增殖与程序性坏死。通过采用SDF-1转染的骨髓MSCs与被缺血缺氧状态诱导的肾小球系膜细胞及肾小管上皮细胞共同培养，观察肾固有细胞的增殖及程序性坏死情况，揭示SDF-1转染促进骨髓MSCs对受损肾小球系膜细胞和肾小管上皮细胞的修复机制是通过抑制肾脏固有细胞程序性坏死而实现。此外，我们分别经肾动脉和外周静脉移植经SDF-1转染的骨髓MSCs，观察肾脏组织的程序性坏死及修复情况，发现在体内模型中，肾动脉移植方式更有助于SDF-1转染的骨髓MSCs归巢至受损肾脏，且骨髓MSCs是通过RIP1/RIP3/MLKL途径抑制慢性肾损伤肾脏固有细胞程序性坏死，从而发挥肾脏修复作用。本项目针对慢性肾病模型深入研究经肾动脉灌注干细胞方式可能更有助于经SDF-1转染的骨髓MSCs在CKD中归巢并发挥促肾脏修复作用，其机制是抑制了肾脏固有细胞程序性坏死。本项目资助发表中文核心论文6篇，SCI 接收3篇。培养硕士研究生5名，博士研究生3名。