基于人动脉粥样硬化单细胞图谱的血管平滑肌表型转化研究

Atherosclerosis is major vascular disease threatening human health, and phenotypic switching of VSMC plays a key role in its pathological process. Past studies have primary focused on directly comparing cellular physiological characteristics and gene expression profiles between the“differentiated” and “dedifferentiated” states of VSMC, as well as the mechanisms underlying VSMC identity maintenance. By contrast, little is known with regard to the cellular heterogeneity of VSMC and the dynamic process of changing through phenotypic switching. By analyzing human coronary arteries in different disease phases of atherosclerosis versus normal arterial tissue at single-cell resolution, we found there are distinct sub-types of VSMC which undergoing dynamic switching in atherosclerosis. Therefore, we propose that sub-types of VSMCs can form a complicated switching system in the process of phenotypic switching, with specific molecular regulation mechanisms to each pathological phase of atherosclerosis. To test our hypothesis, we will first characterize each sub-type of VSMCs, and assembly the dynamic process of phenotypic switching of VSMC given the cellular heterogeneity. Further, we will define the specific signal pathways regulating the dynamic process in each phase of atherosclerosis. Findings from the study will provide insights into the process of phenotypic switching, and will offer novel strategies to prevention and intervention of atherosclerosis.

动脉粥样硬化是严重威胁人类健康的重大血管疾病，其标志性过程是血管平滑肌细胞的表型转化。以往的研究多集中在转化前后细胞生理特性和基因表达谱的对比，及调控表型转化起始的分子机制等，对表型转化这一涉及多种平滑肌细胞亚型复杂动态变化的过程本身知之甚少。利用人冠状动脉粥样硬化不同病理进程样本进行单细胞测序，我们发现，在动脉粥样硬化过程中，存在多种血管平滑肌细胞亚型，各有其特异的基因表达谱，不同亚型的组成比例随病理进程发生动态变化。据此推测，血管平滑肌细胞不同亚型的动态转化在人动脉粥样硬化过程中形成表型转化的复杂过程，转化不同阶段伴随特异的信号通路调控机制。本项目拟基于人动脉粥样硬化单细胞图谱，描述血管平滑肌细胞表型转化动态过程，揭示过程中关键信号通路，探索通过干预关键通路延缓动脉粥样硬化进程的可能性。本研究将帮助我们理解血管平滑肌细胞表型转化复杂过程，为临床治疗动脉粥样硬化疾病提供新的策略。

动脉粥样硬化是严重威胁人类健康的重大血管疾病，血管平滑肌细胞（VSMC）表型转化在其中发挥着重要作用。尽管以往的研究在转化前后细胞生理特性和基因表达谱的对比、及调控表型转化起始的分子机制等方面有所发现，对表型转化这一涉及多种平滑肌细胞亚型复杂动态变化的过程仍然知之甚少。为了更好地理解VSMC表型转化的动态过程，我们利用人冠状动脉粥样硬化不同病理进程样本进行单细胞测序，发现在动脉粥样硬化过程中，存在多种VSMC亚型，各有其特异的基因表达谱，不同亚型的组成比例随病理进程发生动态变化。通过构建VSMC亚型转化的轨迹，挖掘到ETS、NRF和MYB转录因子家族可能是这种转化的上游调控因子。进而通过构建细胞微环境通讯网络，挖掘出可能与VSMC表面受体发生相互作用的重要配体因子，并通过体外实验验证关键配体因子可以影响VSMC的表型转化。这些发现帮助我们更清晰地理解VSMC在病理过程中表型转化的动态过程，为临床干预VSMC表型转化、治疗动脉粥样硬化疾病提供了新的思路和靶点。