长链非编码RNA-BIC调控干细胞向血管平滑肌细胞分化和参与血管损伤后修复-新生内膜形成的作用和机制研究

The neointima formation after vascular injury during which atherosclerosis was basic pathological change has been a hot topic in the field of cardiovascular research. For the source of neointima main component -vascular smooth muscle cells (VSMCs), it has been considered that the proliferation and migration of VSMCs in the central artery is responsible. Rescent studies have shown that Stem/progenitor cells take part in this process through differentiating towards VSMCs. Long non-coding RNA (lncRNA) is one of the newest research hotspots, but none is reported during stem cells differentiation towards VSMCs. Our group found lncRNA-BIC was upregulated during mouse ESCs differentiation towards VSMCs by lncRNA sequencing, which was similar to the results from AS model. Thus, this study aims at revealing the crucial role and underlying mechanism of lncRNA-BIC during ESCs differentiation towards VSMCs and the effect of BIC inducing neointima formation.This may allow us to propose a novel role for BIC as a potential regulator of Vascular development, and also support a latent therapeutic target for AS and restenosis after vascular transplantation.

以动脉粥样硬化（AS）为基本病理改变的血管损伤后修复-新生内膜的形成一直是心血管领域研究热点。对于新生内膜主要成分血管平滑肌细胞（VSMCs）来源l过去一直认为是原来动脉中膜VSMCs增殖、迁移。最新研究认为干/祖细胞能够分化成VSMCs参与这一过程。长链非编码RNA（lncRNA）是最新研究热点，然而在干细胞向VSMCs分化中尚无报道。课题组前期利用已充分建立的小鼠胚胎干细胞（ESCs）向VSMCs分化模型，通过高通量测序手段，发现lncRNA-BIC有明显升高，而在模拟AS形成的模型中也观察到类似变化。因此，本项目拟通过ESCs向VSMCs分化和动物血管导丝损伤模型，明确以下问题：1. lncRNA-BIC在ESCs定向分化VSMCs过程中的作用；2. BIC在血管损伤后修复-新生内膜形成过程中的作用；3.BIC调控ESCs定向分化VSMCs和参与血管损伤后修复的机制。

血管损伤性疾病（代表性疾病为冠心病和移植血管损伤、再狭窄）仍然超越肿瘤，是人类健康的“第一杀手”，机制远未阐明。研究者所在的课题组以及后来的课题组均证明血管壁干/祖细胞向血管平滑肌细胞（VSMCs）分化参与血管损伤后修复及病理性重塑过程。本项目发现多个lncRNA(长链非编码RNA)在小鼠胚胎干细胞（ESCs）向VSMCs分化以及外膜干/祖细胞（APCs）分化VSMCs过程中起着显著作用，这种作用是通过调控miR-30c以及DKK1发生的；此外，本研究还发现BIC及多个潜在lncRNA在冠状动脉造影阴性和阳性患者表达中差距较大，提示可能为潜在标志物或治疗靶点。本研究揭示了BIC参与干细胞分化、血管损伤内膜增生的作用和病理机制，加深了人们对血管损伤性疾病机理的理解，为血管疾病的防治从干细胞和再生医学角度提供新的思路和理论支持。