mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity.
mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity.
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DOI：
10.1038/s41467-022-34763-y
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发表时间：
2022-11-25
影响因子：
16.6
通讯作者：
Chuang, Pao-Tien
中科院分区：
文献类型：
--
作者：
Zhang, Kuan;Yao, Erica;Chuang, Ethan;Chen, Biao;Chuang, Evelyn Y.;Chuang, Pao-Tien
分支器官的形成需要干细胞的连续分化。在这项工作中，我们发现，如果没有 mTOR 复合物 1 (mTORC1) 信号传导，小鼠肺部 SOX2+ 祖细胞衍生的传导气道就无法形成，并被肺囊肿取代。远端 SOX9+ 祖细胞向近端 SOX2+ 细胞转变的近远端模式被破坏。线粒体数量和 ATP 产量减少。线粒体能力受损会导致与 mTORC1 缺陷肺相似的缺陷。这表明 mTORC1 通过调节线粒体能力促进 SOX9+ 祖细胞分化以形成传导气道。令人惊讶的是，在所有突变体中，尽管分支有缺陷，但球囊都是在适当的发育时间从肺囊肿产生的。 SOX9+ 祖细胞还在球囊内分化为 I 型和 II 型肺泡上皮细胞。这些发现强调了干细胞分化过程中选择性利用能量和调节程序来产生哺乳动物肺部的独特结构。肺分支需要祖细胞的分化与形态发生事件相协调。张等人。发现远端 SOX9+ 肺祖细胞中 mTORC1 信号传导的丧失会降低线粒体容量和 ATP 产生，从而破坏传导气道的形成，而不影响气体交换单位的发育。
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 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. Lung branching requires differentiation of progenitor cells to be coordinated with morphogenetic events. Zhang et al. find that loss of mTORC1 signaling in the distal SOX9+ lung progenitors reduces mitochondrial capacity and ATP production, thus disrupting the formation of the conducting airways without affecting the development of the gas exchange unit.
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DOI：
10.1186/s40348-016-0045-7
发表时间：
2016-12
期刊：
Molecular and cellular pediatrics
影响因子：
--
作者：
Chao CM;Moiseenko A;Zimmer KP;Bellusci S
通讯作者：
Bellusci S
影响因子：
5.5
作者：
Jones MR;Chong L;Bellusci S
通讯作者：
Bellusci S
影响因子：
16.6
作者：
Alanis, Denise Martinez;Chang, Daniel R.;Akiyama, Haruhiko;Krasnow, Mark A.;Chen, Jichao
通讯作者：
Chen, Jichao
影响因子：
15.9
作者：
Le Bacquer, Olivier;Petroulakis, Emmanuel;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum
影响因子：
3.5
作者：
Fu W;Hall MN
通讯作者：
Hall MN