Dean Zachary S, Jamilpour Nima, Slepian Marvin J, Wong Pak Kin
Departments of Biomedical Engineering, Mechanical Engineering, and Surgery, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.
ACS Biomater Sci Eng. 2019 Aug 12;5(8):3864-3875. doi: 10.1021/acsbiomaterials.8b01222. Epub 2019 Mar 14.
Collective cell migration is vital to tissue remodeling in wound repair, development, and cancer invasion. Nevertheless, studies on collective cell migration have largely focused on epithelial growth and repair mechanisms and have only recently expanded to explore coordinated metastatic cancer and smooth muscle cell behaviors. The regulatory mechanisms of smooth muscle cell collective migration, such as leader-follower organization and mechanosensitivity, remain poorly understood. In this study, we demonstrate the involvement of leader cells during collective smooth muscle cell migration using dynamic cell tracking and single cell gene expression analysis. Engineered wound models, including ingrowth, outgrowth, and straight edge geometries, along with traction force microscopy and finite element stress mapping reveal that smooth muscle leader cells are enhanced at the wound edge when the intercellular tension near the cell wound boundary is reduced. Pharmacological perturbation further supports the notion that mechanical force negatively regulates the formation of leader cells. The mechanical regulation of collective smooth muscle cell migration via the formation of leader cells may lead to novel treatment strategies for pathogenic smooth muscle cell conditions in the future.
集体细胞迁移对于伤口修复、发育和癌症侵袭过程中的组织重塑至关重要。然而，关于集体细胞迁移的研究主要集中在上皮生长和修复机制，直到最近才扩展到探索转移性癌症和平滑肌细胞的协同行为。平滑肌细胞集体迁移的调控机制，如领导者-跟随者组织和机械敏感性，仍知之甚少。在本研究中，我们使用动态细胞追踪和单细胞基因表达分析，证明了领导者细胞在平滑肌细胞集体迁移过程中的作用。工程化伤口模型，包括向内生长、向外生长和直边几何形状，以及牵引力显微镜和有限元应力映射显示，当细胞伤口边界附近的细胞间张力降低时，平滑肌领导者细胞在伤口边缘增强。药理学扰动进一步支持了机械力负向调节领导者细胞形成的观点。通过形成领导者细胞对平滑肌细胞集体迁移进行机械调节，可能会在未来为致病性平滑肌细胞疾病带来新的治疗策略。
