新型lncRNAs在胚胎干细胞向平滑肌细胞分化过程中的功能机制鉴定及应用探讨

LncRNA are involved in a variety of basic biological processes, such as cardiogenesis, hematopoietic lineage differentiation, and oncogenesis. Better understanding of the complex molecular signals that are evoked during ESC cell differentiation towards vascular smooth muscle cell (VSMCs) may allow specific targeting of their activities to enhance cell differentiation and promote tissue regeneration. In this study we explore for the first time that the functional role of new lncRNAs involved in VSMC differentiation derived from ESC cells, the effect of new lncRNAs to induce angiogenesis has been evaluated in vivo by Matrigel plugs assays. Moreover, we detected the mechanism of new lncRNAs during the differentiation from ESC towards VSMCs.Finally, we detected the expression of those new lncRNAs in coronary artery disease patients.This may allow us to propose a novel role for new lncRNAs as a potential regulator of the phenotypic switch during vascular cell differentiation. This study provides support to the notion that with diligent efforts to understand the molecular mechanisms of vascular cell fate, stem cell regenerative therapy may ultimately become a reality and shift the paradigm to treat cardiovascular disease.

长链非编码RNA是近年来研究最热门的非编码RNA之一,具有多种复杂的生物调控功能，但在干细胞领域中的研究几乎为零。本课题在前期研究基础上，发现数个新型lncRNAs在胚胎干细胞向平滑肌细胞分化过程增高明显，拟从正负两个方面探讨新型lncRNAs在ESC细胞向VSMC细胞定向分化过程中的生物学功能，进而对新型lncRNAs的定位，根据其不同的定位探讨其内在作用机制，同时在小鼠股动脉导丝损伤模型的基础上局部输注含有化学修饰新型lncRNAs抑制剂，从在体水平验证新型lncRNAs对血管损伤后新生内膜形成的影响，最后检测临床冠心病患者血清样本中新型lncRNAs的表达变化，观察其是否能作为冠心病的临床靶点，同时进行SNP分析，在遗传学层面探讨其是否可作为冠心病人群的易感基因。从分子细胞动物到临床水平全面探讨新型lncRNAs在血管损伤及重塑中的应用价值，寻找心血管性疾病新的靶点。

平滑肌细胞 (SMC) 的再生在包括动脉粥样硬化、移植动脉硬化损伤后修复在内的血管发病机制中起关键作用。最近的研究支持 Sca1+ 干/祖细胞 (SPC) 在严重损伤后产生从头平滑肌细胞，并且与先前存在的平滑肌相比更有效地扩张，但其潜在机制缺乏进一步探索。在这里，我们使用遗传谱系追踪小鼠来揭示调节 Sca1+ SPC 的机制。我们发现 Sca1+ SPCs 在小鼠移植血管中产生 SMCs 作为血管修复，但 lncRNA Malat1 缺乏上调了导致新内膜和血管狭窄中过度 SMC 积累的过程。蛋白质阵列测序将 Rap1 信号通路区分为 Malat1 的靶标。这些发现提供了证据，证明 Sca1+-SMC 转变的动态平衡在血管重塑中起关键作用。 LncRNA Malat1 作为一种强有力的调节剂可能是血管修复和狭窄的潜在治疗靶点。