Cao Jingli, Wang Jinhu, Jackman Christopher P, Cox Amanda H, Trembley Michael A, Balowski Joseph J, Cox Ben D, De Simone Alessandro, Dickson Amy L, Di Talia Stefano, Small Eric M, Kiehart Daniel P, Bursac Nenad, Poss Kenneth D
Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA; Regeneration Next, Duke University, Durham, NC 27710, USA.
Regeneration Next, Duke University, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
Dev Cell. 2017 Sep 25;42(6):600-615.e4. doi: 10.1016/j.devcel.2017.08.024.
Mechanisms that control cell-cycle dynamics during tissue regeneration require elucidation. Here we find in zebrafish that regeneration of the epicardium, the mesothelial covering of the heart, is mediated by two phenotypically distinct epicardial cell subpopulations. These include a front of large, multinucleate leader cells, trailed by follower cells that divide to produce small, mononucleate daughters. By using live imaging of cell-cycle dynamics, we show that leader cells form by spatiotemporally regulated endoreplication, caused primarily by cytokinesis failure. Leader cells display greater velocities and mechanical tension within the epicardial tissue sheet, and experimentally induced tension anisotropy stimulates ectopic endoreplication. Unbalancing epicardial cell-cycle dynamics with chemical modulators indicated autonomous regenerative capacity in both leader and follower cells, with leaders displaying an enhanced capacity for surface coverage. Our findings provide evidence that mechanical tension can regulate cell-cycle dynamics in regenerating tissue, stratifying the source cell features to improve repair.
在组织再生过程中控制细胞周期动态的机制需要阐明。我们在斑马鱼中发现，心脏的间皮覆盖层——心外膜的再生由两个表型不同的心外膜细胞亚群介导。其中包括一群大型多核的先导细胞，后面跟着进行分裂产生小的单核子代细胞的跟随细胞。通过对细胞周期动态进行实时成像，我们发现先导细胞通过主要由胞质分裂失败导致的时空调控的核内复制形成。先导细胞在心外膜组织片中表现出更高的速度和机械张力，实验诱导的张力各向异性刺激异位核内复制。用化学调节剂使心外膜细胞周期动态失衡表明先导细胞和跟随细胞都具有自主再生能力，其中先导细胞在表面覆盖方面表现出更强的能力。我们的研究结果提供了证据，证明机械张力可以调节再生组织中的细胞周期动态，区分源细胞特征以改善修复。
