钙闪烁引导细胞迁移

Calcium Flickers Steer Cell Migration

细胞迁移在个体发育、组织重塑、损伤后再生以及肿瘤发生等过程中发挥着重要作用。细胞迁移过程受钙信号调控,但长期困扰这一领域的一个悖论是,为何引导迁移的细胞前沿区钙信号反而较低。本研究采用高分辨率共聚焦钙离子荧光成像技术,在迁移的成纤维细胞中首次探测到动态微区钙信号——"钙闪烁"(calcium flickers)。钙闪烁富集于细胞迁移前沿,与静态钙离子梯度恰恰相反。产生钙闪烁的分子机制涉及两类钙离子通道,即细胞表面TRPM7牵张激活通道和内质网膜上的IP3受体。在趋化因子PDGF作用下,引导前沿中钙闪烁呈不对称分布,从而促进迁移细胞的转向。研究结果不仅完美地解释了上述悖论,同时揭示了微区钙信号如何通过精细的时空整合调节细胞迁移、趋化反应等复杂的生命过程。

Directional movement is a property common to all cell types during development and is critical to tissue remodelling and regeneration after damage. In migrating cells, calcium has a muhifunctional role in directional sensing, cytoskeleton redistribution, traction force generation, and relocation of focal adhesions. Here we visualize high-calcium microdomains （ ‘calcium flickers＇ ） and their patterned activation in migrating human embryonic lung fibroblasts. Calcium flicker activity is dually coupled to membrane tension （by means of TRPMT, a stretch-activated Ca^2＋ -permeant channel of the transient receptor potential superfamily8） and chemoattractant signal transduction （ by means of type 2 inositol- 1,4,5-trisphosphate receptors）. Interestingly, calcium flickers are most active at the leading lamella of migrating cells, displaying a 4 ： 1 front-to-rear polarization opposite to the global calcium gradient. When exposed to a platelet-derived growth factor gradient perpendicular to cell movement, asymmetric calcium flicker activity develops across the lamella and promotes the turning of migrating fibroblasts. These findings show how the ex- quisite spatiotemporal organization of calcium microdomains can orchestrate complex cellular processes such as cell migration.