Mechanical stretch triggers rapid epithelial cell division through Piezo1.
Mechanical stretch triggers rapid epithelial cell division through Piezo1.
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DOI：
10.1038/nature21407
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发表时间：
2017-03-02
期刊：
影响因子：
64.8
通讯作者：
Rosenblatt J
中科院分区：
文献类型：
--
作者：
Gudipaty SA;Lindblom J;Loftus PD;Redd MJ;Edes K;Davey CF;Krishnegowda V;Rosenblatt J
尽管上皮细胞作为它们所包裹的器官的屏障，但它们的周转速度在体内是最快的。然而，上皮细胞分裂必须与细胞死亡紧密相连，以保持屏障功能并防止肿瘤形成。死亡细胞的数量如何与分裂细胞的数量相匹配以保持恒定的数量？我们之前发现，当上皮细胞变得过于拥挤时，它们会激活拉伸激活通道Piezo 1，从而引发细胞挤出，随后死亡。相反，是什么控制上皮细胞分裂，以平衡稳态下的细胞死亡？在这里，我们发现细胞分裂发生在低细胞密度的区域，在那里上皮细胞被拉伸。通过实验拉伸上皮细胞，我们发现机械拉伸本身通过激活相同的Piezo 1通道迅速刺激细胞分裂。为此，牵张触发细胞在G2早期暂停以激活钙依赖性ERK 1/2磷酸化，从而激活驱动细胞进入有丝分裂所必需的细胞周期蛋白B转录。虽然上皮细胞分裂和细胞挤出都需要Piezo 1处于稳态，但机械力的类型控制着结果：拉伸诱导细胞分裂，而拥挤诱导挤出。Piezo 1依赖性钙瞬变如何激活两个相反的过程可能取决于Piezo 1在何处以及如何被激活，因为它随着细胞密度的增加而在不同的亚细胞位点积累。在细胞分裂的稀疏上皮区域，Piezo 1定位于质膜和细胞质，而在细胞突出的密集区域，它形成大的细胞质聚集体。由于Piezo 1可以感知机械拥挤和拉伸，因此它可以作为一种稳态传感器来控制上皮细胞数量，从而触发拥挤区域的挤出/凋亡和稀疏区域的细胞分裂。
Despite acting as a barrier for the organs they encase, epithelial cells turnover at some of the fastest rates in the body. Yet, epithelial cell division must be tightly linked to cell death to preserve barrier function and prevent tumour formation. How do the number of dying cells match those dividing to maintain constant numbers? We previously found that when epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die. Conversely, what controls epithelial cell division to balance cell death at steady state? Here, we find that cell division occurs in regions of low cell density, where epithelial cells are stretched. By experimentally stretching epithelia, we find that mechanical stretch itself rapidly stimulates cell division through activation of the same Piezo1 channel. To do so, stretch triggers cells paused in early G2 to activate calcium-dependent ERK1/2 phosphorylation that activates cyclin B transcription necessary to drive cells into mitosis. Although both epithelial cell division and cell extrusion require Piezo1 at steady state, the type of mechanical force controls the outcome: stretch induces cell division whereas crowding induces extrusion. How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated since it accumulates in different subcellular sites with increasing cell density. In sparse epithelial regions where cells divide, Piezo1 localizes to the plasma membrane and cytoplasm whereas in dense regions where cells extrude, it forms large cytoplasmic aggregates. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers, triggering extrusion/apoptosis in crowded regions and cell division in sparse regions.