Yan Yujie, Wang Yuhang, Chu Julia S, Yang Li, Li Xian, Li Song
College of Medical Informatics, Chongqing Medical University, Chongqing 400016, China.
Department of Neurology, University of California, San Francisco, CA 94143, USA.
Cells. 2025 Apr 17;14(8):611. doi: 10.3390/cells14080611.
Multipotent vascular stem cells (MVSCs) are found in the vascular wall and surrounding tissues and possess the ability to differentiate into mesenchymal lineages. Previous studies have shown that MVSCs can be activated in response to vascular injury and differentiate into vascular smooth muscle cells (SMCs), contributing to vascular remodeling and microvessel formation. However, it remains unclear as to whether and how microenvironmental changes in the extracellular matrix, such as substrate stiffness, modulates MVSC differentiation under pathological conditions. This study demonstrated that MVSCs cultured on stiff substrates exhibited increased cell spreading, stronger cell adhesion, and a higher expression of SMC markers, including myosin heavy chain (MHC), myocardin (MYCD), calponin 1 (CNN1), and smooth muscle α-actin (SMA). In contrast, MVSCs on soft substrates showed an elevated expression of the chondrogenic markers aggrecan 1 (AGC1) and collagen-II (COL2A1). The presence of TGF-β1 further increased the expression of SMC markers on stiff substrates and chondrogenic markers on the soft substrates. Collectively, these results establish substrate stiffness as a key regulator of MVSC lineage commitment through cytoskeletal reorganization, with TGF-β1 acting as a biochemical amplifier. Our findings highlight the substrate-stiffness-dependent differentiation of MVSCs and provide mechanistic insights into the role of MVSCs in vascular remodeling during atherosclerosis development and blood vessel regeneration.
多能血管干细胞（MVSCs）存在于血管壁和周围组织中，具有分化为间充质谱系的能力。先前的研究表明，MVSCs可在血管损伤时被激活，并分化为血管平滑肌细胞（SMC），从而促进血管重塑和微血管形成。然而，在病理条件下，细胞外基质的微环境变化，如底物硬度，是否以及如何调节MVSC分化仍不清楚。本研究表明，在硬底物上培养的MVSCs表现出细胞铺展增加、细胞黏附增强以及SMC标志物的表达升高，这些标志物包括肌球蛋白重链（MHC）、心肌素（MYCD）、钙调蛋白1（CNN1）和平滑肌α-肌动蛋白（SMA）。相比之下，在软底物上的MVSCs软骨生成标志物聚集蛋白聚糖1（AGC1）和胶原蛋白II（COL2A1）的表达升高。TGF-β1的存在进一步增加了硬底物上SMC标志物以及软底物上软骨生成标志物的表达。总体而言，这些结果确定底物硬度是通过细胞骨架重组对MVSC谱系定向的关键调节因子，而TGF-β1作为一种生化放大器。我们的研究结果突出了MVSCs依赖底物硬度的分化，并为MVSCs在动脉粥样硬化发展和血管再生过程中血管重塑中的作用提供了机制性见解。
