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. Examine the difference of gene expression among Rptor-, Tfam-, Cox10-deficient and their littermate control lungs分支状器官的形成依赖于干细胞的时序性分化。本研究发现，若缺乏雷帕霉素靶蛋白复合物1（mTOR complex 1, mTORC1）信号通路，源自小鼠肺部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+祖细胞向近端SOX2+细胞转化以实现近-远端模式构建的过程受到破坏。线粒体数量与ATP生成量均出现下降。线粒体功能受损会引发与mTORC1缺陷肺部相似的发育缺陷。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，但所有突变体的肺囊肿仍可在正常发育时相内形成肺小囊。肺小囊内的SOX9+祖细胞还可分化为肺泡上皮I型与II型细胞。本研究结果凸显了干细胞分化过程中能量与调控程序的选择性利用，这对于构建哺乳动物肺部的不同结构至关重要。本研究同时分析了Rptor缺陷型、Tfam缺陷型、Cox10缺陷型小鼠肺部与其同窝对照肺部之间的基因表达差异。