Espinosa-Diez Cristina, Mandi Varun, Du Mingyuan, Liu Mingjun, Gomez Delphine
Pittsburgh Heart, Lung, Blood, and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pa.
Department of Vascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.
JVS Vasc Sci. 2021 May 15;2:136-148. doi: 10.1016/j.jvssci.2021.02.002. eCollection 2021.
Our knowledge of the contribution of vascular smooth muscle cells (SMCs) to atherosclerosis has greatly advanced in the previous decade with the development of techniques allowing for the unambiguous identification and phenotypic characterization of SMC populations within the diseased vascular wall. By performing fate mapping or single-cell transcriptomics studies, or a combination of both, the field has made key observations: SMCs populate atherosclerotic lesions by the selective expansion and investment of a limited number of medial SMCs, which undergo profound and diverse modifications of their original phenotype and function. Thus, if SMCs residing within atherosclerotic lesions and contributing to the disease are clones, they are not carbon copies and can play atheroprotective or atheropromoting roles, depending on the nature of their phenotypic transitions. Tremendous progress has been made in identifying the transcriptional mechanisms biasing SMC fate. In the present review, we have summarized the recent advances in characterizing SMC investment and phenotypic diversity and the molecular mechanisms controlling SMC fate in atherosclerotic lesions. We have also discussed some of the remaining questions associated with these breakthrough observations. These questions include the underlying mechanisms regulating the phenomenon of SMC oligoclonal expansion; whether single-cell transcriptomics is reliable and sufficient to ascertain SMC functions and contributions during atherosclerosis development and progression; and how SMC clonality and phenotypic plasticity affects translational research and the therapeutic approaches developed to prevent atherosclerosis complications. Finally, we have discussed the complementary approaches the field should lean toward by combining single-cell phenotypic categorization and functional studies to understand further the complex SMC behavior and contribution in atherosclerosis.
在过去十年中，随着技术的发展，我们对血管平滑肌细胞（SMC）在动脉粥样硬化中的作用的认识有了很大进展，这些技术能够明确识别病变血管壁内的SMC群体并对其进行表型特征分析。通过进行命运图谱分析或单细胞转录组学研究，或两者结合，该领域取得了关键发现：SMC通过有限数量的中膜SMC的选择性扩增和增殖来填充动脉粥样硬化病变，这些中膜SMC的原始表型和功能会发生深刻而多样的改变。因此，如果存在于动脉粥样硬化病变中并导致疾病的SMC是克隆细胞，它们也并非完全相同的复制品，而是根据其表型转变的性质发挥抗动脉粥样硬化或促动脉粥样硬化的作用。在确定偏向SMC命运的转录机制方面已经取得了巨大进展。在本综述中，我们总结了在表征SMC增殖和表型多样性以及控制动脉粥样硬化病变中SMC命运的分子机制方面的最新进展。我们还讨论了与这些突破性发现相关的一些遗留问题。这些问题包括调节SMC寡克隆扩增现象的潜在机制；单细胞转录组学是否可靠且足以确定SMC在动脉粥样硬化发生和发展过程中的功能及作用；以及SMC克隆性和表型可塑性如何影响转化研究和为预防动脉粥样硬化并发症而开发的治疗方法。最后，我们讨论了该领域应倾向采用的互补方法，即将单细胞表型分类与功能研究相结合，以进一步了解SMC在动脉粥样硬化中的复杂行为和作用。
