The development and plasticity of alveolar type 1 cells
The development and plasticity of alveolar type 1 cells
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DOI：
10.1242/dev.130005
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发表时间：
2016-01-01
期刊：
影响因子：
4.6
通讯作者：
Chen, Jichao
中科院分区：
文献类型：
--
作者：
Yang, Jun;Hernandez, Belinda J.;Chen, Jichao
肺泡1型（AT1）细胞覆盖了95%的气体交换表面，它们非常薄，有利于被动气体扩散。这些高度特化细胞的发育及其与蜂窝状肺泡结构形成的协调机制尚不清楚。利用新的基于标记的立体学和单细胞成像方法，我们发现小鼠肺中的AT1细胞通过非增殖的两步过程形成膨胀的薄细胞延伸，同时保持细胞的可塑性。在平坦化步骤中，AT1细胞经历分子规范和重塑细胞连接，同时保持与邻近上皮细胞的连接。在折叠步骤中，AT1细胞的大小增加了10倍以上，并经历了与毛细血管和次级隔膜形成相匹配的细胞形态发生，导致单个AT1细胞跨越多个肺泡。此外，AT1细胞是VEGFA的意外来源，它们的正常发育是肺泡血管生成所必需的。值得注意的是，大多数AT1细胞在异位SOX2表达时增殖，并经历阶段依赖性的细胞命运重编程。这些结果证明AT1细胞在肺泡成熟过程中具有结构和信号作用，并能退出其终末分化的非增殖状态。我们的研究结果表明，AT1细胞可能是早产相关肺部疾病发病机制和治疗的新靶点。
Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination with the formation of the honeycomb-like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming. These results provide evidence that AT1 cells have both structural and signaling roles in alveolar maturation and can exit their terminally differentiated non-proliferative state. Our findings suggest that AT1 cells might be a new target in the pathogenesis and treatment of lung diseases associated with premature birth.