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

Theodore T. Ho, Matthew R. Warr, Emmalee R. Adelman, Olivia M. Lansinger, Johanna Flach, Evgenia V. Verovskaya, Maria E. Figueroa and Emmanuelle Passegué ()
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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
Emmanuelle Passegué: The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California San Francisco

Nature, 2017, vol. 543, issue 7644, 205-210

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21388

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