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

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  • Kuan Zhang

    (University of California)

  • Erica Yao

    (University of California)

  • Ethan Chuang

    (University of California)

  • Biao Chen

    (University of California)

  • Evelyn Y. Chuang

    (University of California)

  • Pao-Tien Chuang

    (University of California)

Abstract

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.

Suggested Citation

  • Kuan Zhang & Erica Yao & Ethan Chuang & Biao Chen & Evelyn Y. Chuang & Pao-Tien Chuang, 2022. "mTORC1 signaling facilitates differential stem cell differentiation to shape the developing murine lung and is associated with mitochondrial capacity," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34763-y
    DOI: 10.1038/s41467-022-34763-y
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    References listed on IDEAS

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    1. Ross J. Metzger & Ophir D. Klein & Gail R. Martin & Mark A. Krasnow, 2008. "The branching programme of mouse lung development," Nature, Nature, vol. 453(7196), pages 745-750, June.
    2. Denise Martinez Alanis & Daniel R. Chang & Haruhiko Akiyama & Mark A. Krasnow & Jichao Chen, 2014. "Two nested developmental waves demarcate a compartment boundary in the mouse lung," Nature Communications, Nature, vol. 5(1), pages 1-15, September.
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