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Autophagy maintains the metabolism and function of young and old stem cells

Author

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  • Theodore T. Ho

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

  • Matthew R. Warr

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

  • Emmalee R. Adelman

    (University of Michigan School of Medicine)

  • Olivia M. Lansinger

    (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)

  • Evgenia V. Verovskaya

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

  • Maria E. Figueroa

    (University of Michigan School of Medicine
    † Present addresses: Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA (M.E.F.); Department of Genetics and Development, Columbia Stem Cell Initiative, Columbia University School of Medicine, New York, New York 10032, USA (E.P.).)

  • Emmanuelle Passegué

    (The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco
    † Present addresses: Department of Human Genetics, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA (M.E.F.); Department of Genetics and Development, Columbia Stem Cell Initiative, Columbia University School of Medicine, New York, New York 10032, USA (E.P.).)

Abstract

With age, haematopoietic stem cells lose their ability to regenerate the blood system, and promote disease development. Autophagy is associated with health and longevity, and is critical for protecting haematopoietic stem cells from metabolic stress. Here we show that loss of autophagy in haematopoietic stem cells causes accumulation of mitochondria and an activated metabolic state, which drives accelerated myeloid differentiation mainly through epigenetic deregulations, and impairs haematopoietic stem-cell self-renewal activity and regenerative potential. Strikingly, most haematopoietic stem cells in aged mice share these altered metabolic and functional features. However, approximately one-third of aged haematopoietic stem cells exhibit high autophagy levels and maintain a low metabolic state with robust long-term regeneration potential similar to healthy young haematopoietic stem cells. Our results demonstrate that autophagy actively suppresses haematopoietic stem-cell metabolism by clearing active, healthy mitochondria to maintain quiescence and stemness, and becomes increasingly necessary with age to preserve the regenerative capacity of old haematopoietic stem cells.

Suggested Citation

  • Theodore T. Ho & Matthew R. Warr & Emmalee R. Adelman & Olivia M. Lansinger & Johanna Flach & Evgenia V. Verovskaya & Maria E. Figueroa & Emmanuelle Passegué, 2017. "Autophagy maintains the metabolism and function of young and old stem cells," Nature, Nature, vol. 543(7644), pages 205-210, March.
    • Handle: RePEc:nat:nature:v:543:y:2017:i:7644:d:10.1038_nature21388
    DOI: 10.1038/nature21388
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    Cited by:

    1. Kyung Mok Kim & Anna Mura-Meszaros & Marie Tollot & Murali Shyam Krishnan & Marco Gründl & Laura Neubert & Marco Groth & Alejo Rodriguez-Fraticelli & Arthur Flohr Svendsen & Stefano Campaner & Nico An, 2022. "Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. 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.
    3. 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.
    4. Jaishree Tripathi & Michal Stoklasa & Sourav Nayak & Kay En Low & Erica Qian Hui Lee & Quang Huy Duong Tien & Laurent Rénia & Benoit Malleret & Zbynek Bozdech, 2024. "The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular quiescence/senescence and drug resilience," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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