Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds
Release of cellular tension signals self-restorative ventral lamellipodia to heal barrier micro-wounds
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DOI：
10.1083/jcb.201209077
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发表时间：
2013-04-29
影响因子：
7.8
通讯作者：
Carman, Christopher V.
中科院分区：
文献类型：
--
作者：
Martinelli, Roberta;Kamei, Masataka;Carman, Christopher V.
细胞屏障感知和响应完整性破坏的基本机制仍然知之甚少。尽管血管内皮结构脆弱且暴露于破坏性菌株，但仍表现出强大的屏障功能。我们发现，为了响应白细胞迁移引起的微米级破坏，内皮细胞产生独特的腹侧板状伪足，通过整合素向并穿过这些“微伤口”传播以闭合它们。这种新颖的肌动蛋白重塑活性逐渐连续治愈多个微伤口，并在此过程中改变方向。机械探针诱导的内皮细胞和上皮细胞的微损伤表明，腹侧板状伪足的形成是对力不平衡和特别是等长张力丧失的反应。腹侧板状伪足富含 Rac1 效应子 cortactin、IQGAP 和 p47Phox，并表现出过氧化氢的局部产生。与 4 月 2 日和 3 月一起，这些都是有效微伤口愈合所需的功能。我们提出，屏障破坏被检测为等长张力/力卸载的局部释放，这与活性氧依赖性自我恢复肌动蛋白重塑动力学直接耦合。
Basic mechanisms by which cellular barriers sense and respond to integrity disruptions remain poorly understood. Despite its tenuous structure and constitutive exposure to disruptive strains, the vascular endothelium exhibits robust barrier function. We show that in response to micrometer-scale disruptions induced by transmigrating leukocytes, endothelial cells generate unique ventral lamellipodia that propagate via integrins toward and across these "micro-wounds" to close them. This novel actin remodeling activity progressively healed multiple micro-wounds in succession and changed direction during this process. Mechanical probe-induced micro-wounding of both endothelia and epithelia suggests that ventral lamellipodia formed as a response to force imbalance and specifically loss of isometric tension. Ventral lamellipodia were enriched in the Rac1 effectors cortactin, IQGAP, and p47Phox and exhibited localized production of hydrogen peroxide. Together with Apr2/3, these were functionally required for effective micro-wound healing. We propose that barrier disruptions are detected as local release of isometric tension/force unloading, which is directly coupled to reactive oxygen species-dependent self-restorative actin remodeling dynamics.