NBR1介导自噬调控黏着斑解离在MSC归巢修复ARDS中的作用和机制研究

Mesenchymal stem cell (MSC) could promote the repairation of acute respiratory distress syndrome (ARDS). However, the homing rate to injured lung tissue is low. In the previous study, we found that Ang II-AT2R promoted MSC migration primarily through focal adhesion formation. Interestingly, recent studies demonstrated that NBR1-mediated selective autophagy could affect focal adhesion formation and cell migration. What’s more, Ang II inhibits autophagy mainly through the AT2R receptor. Therefore, we speculate that Ang II-AT2R inhibits NBR1-mediated autophagy, thereby inhibiting the diasssembly of focal adhesions and promoting the homing of MSC. In this study, we try to make clear that Ang II promotes the diasssembly of focal adhesions mainly through AT2R-mediated autophagy. Furthermore, we regulate the expression of NBR1 to clarify the role of NBR1 in Ang II-induced focal adhesion dissociation. Finally, we try to use animal-level evidences to demonstrate that MSC downregulated with NBR1 receptor could promotes MSC homing to damaged lung tissue, ultimately contributing to the repairation of lung injury. In this study, we explore the mechanism by which Ang II promotes the homing of MSCs to injured lung and provide a new target for the optimization of MSCs for ARDS treatment.

间充质干细胞（MSC）能够促进急性呼吸窘迫综合征（ARDS）的修复，而其向损伤肺组织归巢率低限制其修复效果的提高。申请者在前期研究中发现ARDS时肺部水平升高的AngII主要通过MSC表面的AT2R促进黏着斑的形成增加进而促进MSC向损伤肺组织归巢。而近期研究发现NBR1受体介导的选择性自噬能够促进黏着斑的解离，从而抑制细胞迁移，并且AngII主要通过AT2R受体抑制自噬活动。因此，我们推测AngII-AT2R抑制NBR1介导的自噬，从而抑制黏着斑的解离，促进MSC的归巢。本研究拟体外明确AngII主要通过AT2R抑制自噬减少黏着斑的解离。进一步调控NBR1的表达，明确NBR1在AngII影响黏着斑解离中的作用。最后动物实验验证干扰MSC的NBR1受体能够促进MSC向损伤肺组织归巢，最终促进肺损伤的修复。本研究通过探讨AngII促进MSC归巢的机制，为优化MSC治疗ARDS提供新靶点。

间充质干细胞（MSC）能够促进急性呼吸窘迫综合征（ARDS）的修复，而其向损伤肺组织归巢率低限制其修复效果的提高。前期研究中发现ARDS时肺部水平升高的Ang II主要通过MSC表面的AT2R促进黏着斑的形成增加进而促进MSC向损伤肺组织归巢。而近期研究发现NBR1受体介导的选择性自噬能够促进黏着斑的解离，从而抑制细胞迁移，并且Ang II主要通过AT2R受体抑制自噬活动，但Ang II-AT2R对MSCs自噬的影响尚不明确。本研究在体外实验证实Ang II可以通过AT2R抑制MSCs的自噬。并且Ang II通过AT2R可以抑制自噬选择性受体NBR1的表达，经过调控NBR1的表达后，可见干扰NBR1可明显促进细胞的迁移，反之，过表达NBR1可显著抑制细胞的迁移。进一步研究发现干扰NBR1的表达可提高FAK的水平，过表达NBR1可减少FAK斑点的数量。共同表明Ang II-AT2R主要通过抑制NBR1的表达来抑制自噬，从而减少FAK的降解，促进其数量增加，最终促进MSC的迁移。本研究进一步通过慢病毒介导NBR1过表达和干扰进行骨髓MSCs的转导，在LPS诱导的ARDS小鼠模型的基础上，通过观察NBR1过表达和干扰的MSCs在ARDS小鼠肺内的存留以及肺损伤的修复，明确干扰NBR1的MSCs移植入急性肺损伤小鼠体内对其向损伤肺组织的迁移以及对肺损伤修复的影响。结果表明干扰NBR1可显著增强MSCs的迁移能力并增加其在ALI损伤肺组织内的存留，从而更好的促进肺内屏障功能的恢复，抑制肺内的炎症反应，促进肺损伤的修复。本研究揭示了促进MSCs有效归巢至损伤肺组织的新靶点，从而为优化MSCs治疗ALI/ARDS的效果提供了新的方向。

内容获取失败，请点击重试