PDF(Pubmed)
Abstract：
Tissue homeostasis and disease states rely on the formation of new blood vessels through angiogenic sprouting, which is tightly regulated by the properties of the surrounding extracellular matrix. While physical cues, such as matrix stiffness or degradability, have evolved as major regulators of cell function in tissue microenvironments, it remains unknown whether and how physical cues regulate endothelial cell migration during angiogenesis. To investigate this, a biomimetic model of angiogenic sprouting inside a tunable synthetic hydrogel is created. It is shown that endothelial cells sense the resistance of the surrounding matrix toward proteolytic cleavage and respond by adjusting their migration phenotype. The resistance cells encounter is impacted by the number of covalent matrix crosslinks, crosslink degradability, and the proteolytic activity of cells. When matrix resistance is high, cells switch from a collective to an actomyosin contractility-dependent single cellular migration mode. This switch in collectivity is accompanied by a major reorganization of the actin cytoskeleton, where stress fibers are no longer visible, and F-actin aggregates in large punctate clusters. Matrix resistance is identified as a previously unknown regulator of angiogenic sprouting and, thus, provides a mechanism by which the physical properties of the matrix impact cell migration modes through cytoskeletal remodeling.
摘要：
组织稳态和疾病状态依赖于通过血管生成发芽形成新血管，受周围细胞外基质的特性严格调节。虽然物理线索，如基体刚度或降解性，已经发展成为组织微环境中细胞功能的主要调节因子，目前尚不清楚物理线索是否以及如何在血管生成过程中调节内皮细胞迁移。为了调查这一点，在可调的合成水凝胶内形成血管生成发芽的仿生模型。结果表明，内皮细胞感知周围基质对蛋白水解裂解的抵抗力，并通过调节其迁移表型做出反应。电阻细胞遭遇受到共价基质交联的数量的影响，交联降解性，和细胞的蛋白水解活性。当基体电阻较高时，细胞从集体转变为依赖于肌动球蛋白收缩性的单细胞迁移模式。这种集体转换伴随着肌动蛋白细胞骨架的重大重组，应力纤维不再可见，和F-肌动蛋白聚集在大的点状簇中。基质抗性被确定为先前未知的血管生成发芽调节剂，因此，提供了基质的物理性质通过细胞骨架重塑影响细胞迁移模式的机制。
