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FOXO3A directs a protective autophagy program in haematopoietic stem cells

Author

Listed:
  • Matthew R. Warr

    (The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco)

  • Mikhail Binnewies

    (The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco)

  • Johanna Flach

    (The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco)

  • Damien Reynaud

    (The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco)

  • Trit Garg

    (The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco)

  • Ritu Malhotra

    (University of California)

  • Jayanta Debnath

    (University of California)

  • Emmanuelle Passegué

    (The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco)

Abstract

Blood production is ensured by rare, self-renewing haematopoietic stem cells (HSCs). How HSCs accommodate the diverse cellular stresses associated with their life-long activity remains elusive. Here we identify autophagy as an essential mechanism protecting HSCs from metabolic stress. We show that mouse HSCs, in contrast to their short-lived myeloid progeny, robustly induce autophagy after ex vivo cytokine withdrawal and in vivo calorie restriction. We demonstrate that FOXO3A is critical to maintain a gene expression program that poises HSCs for rapid induction of autophagy upon starvation. Notably, we find that old HSCs retain an intact FOXO3A-driven pro-autophagy gene program, and that ongoing autophagy is needed to mitigate an energy crisis and allow their survival. Our results demonstrate that autophagy is essential for the life-long maintenance of the HSC compartment and for supporting an old, failing blood system.

Suggested Citation

  • Matthew R. Warr & Mikhail Binnewies & Johanna Flach & Damien Reynaud & Trit Garg & Ritu Malhotra & Jayanta Debnath & Emmanuelle Passegué, 2013. "FOXO3A directs a protective autophagy program in haematopoietic stem cells," Nature, Nature, vol. 494(7437), pages 323-327, February.
    • Handle: RePEc:nat:nature:v:494:y:2013:i:7437:d:10.1038_nature11895
    DOI: 10.1038/nature11895
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    Cited by:

    1. Florisela Herrejon Chavez & Hanzhi Luo & Paolo Cifani & Alli Pine & Eren L. Chu & Suhasini Joshi & Ersilia Barin & Alexandra Schurer & Mandy Chan & Kathryn Chang & Grace Y. Q. Han & Aspen J. Pierson &, 2023. "RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. WeiChao Hao & MeiJuan Dian & Ying Zhou & QiuLing Zhong & WenQian Pang & ZiJian Li & YaYan Zhao & JiaCheng Ma & XiaoLin Lin & RenRu Luo & YongLong Li & JunShuang Jia & HongFen Shen & ShiHao Huang & Gua, 2022. "Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    3. Hongna Zuo & Aiwei Wu & Mingwei Wang & Liquan Hong & Hu Wang, 2024. "tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Yumin Liu & Linjuan Shi & Yifan Chen & Sifan Luo & Yuehang Chen & Hongtian Chen & Wenlang Lan & Xun Lu & Zhan Cao & Zehua Ye & Jinping Li & Bo Yu & Elaine Dzierzak & Zhuan Li, 2024. "Autophagy regulates the maturation of hematopoietic precursors in the embryo," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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