mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity

Formation of branched organs requires sequential differentiation of stem cells. In this work, we find that the conducting airways derived from SOX2+ progenitors in the murine lungs fail to form without mTOR complex 1 (mTORC1) signaling and are replaced by lung cysts. Proximal-distal patterning through transitioning of distal SOX9+ progenitors to the proximal SOX2+ cells is disrupted. Mitochondria number and ATP production are reduced. Compromised mitochondrial capacity results in a similar defect as that in mTORC1-deficient lungs. This suggests that mTORC1 promotes differentiation of SOX9+ progenitors to form the conducting airways by modulating mitochondrial capacity. Surprisingly, in all mutants saccules are produced from lung cysts at the proper developmental time despite defective branching. SOX9+ progenitors also differentiate into alveolar epithelial type I and type II cells within saccules. These findings highlight selective utilization of energy and regulatory programs during stem cell differentiation to produce distinct structures of the mammalian lungs. Examination the gene expression difference between Control and mTORC1 deficient lungs分支器官的形成依赖于干细胞的时序性分化。本研究发现，若缺失哺乳动物雷帕霉素靶蛋白复合物1（mTOR complex 1, mTORC1）信号通路，源自小鼠肺内SOX2阳性（SOX2+）祖细胞的传导气道无法正常形成，并会被肺囊肿所替代。远端SOX9阳性（SOX9+）祖细胞向近端SOX2+细胞转化以构建近-远端模式的过程遭到破坏。线粒体数量与ATP生成均出现下降。线粒体功能受损会引发与mTORC1缺陷肺组织相似的发育缺陷。这表明mTORC1可通过调控线粒体功能，促进SOX9+祖细胞分化以形成传导气道。令人意外的是，尽管分支发育存在缺陷，所有突变体仍能在正常发育时段从肺囊肿中产生肺泡囊。SOX9+祖细胞亦可在肺泡囊中分化为肺泡上皮Ⅰ型与Ⅱ型细胞。本研究结果揭示，在干细胞分化过程中，能量代谢与调控程序的选择性利用，是哺乳动物肺脏形成不同结构的关键基础。本研究同时对对照组与mTORC1缺陷型肺组织的基因表达差异进行了分析。