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Cell Stem Cell. 2017 Dec 7;21(6):806-818.e5. doi: 10.1016/j.stem.2017.11.008.

mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance.

Author information

1
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
2
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA.
3
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Mount Holyoke College, South Hadley, MA 01075, USA.
4
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Medicine, Columbia University, New York, NY 10032, USA.
6
Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94304, USA.
7
Department of Anatomy, UCSF School of Medicine, San Francisco, CA 94117, USA.
8
Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, CA 94304, USA; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research, USC, Los Angeles, CA 90033, USA.
9
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA 94945-1400, USA; Immunology Discovery, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA; Leibniz Institute on Aging, Fritz Lipmann Institute, Jena 07745, Germany. Electronic address: jasperh@gene.com.

Abstract

The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling. Although this activation is required for SCs to rapidly proliferate in response to damage, repeated rounds of damage lead to SC loss. Consistently, age-related SC loss in the mouse trachea and in muscle can be prevented by pharmacologic or genetic inhibition, respectively, of mammalian target of rapamycin complex 1 (mTORC1) signaling. These findings highlight an evolutionarily conserved role of TOR signaling in SC function and identify repeated rounds of mTORC1 activation as a driver of age-related SC decline.

KEYWORDS:

Drosophila; aging; intestine; mTOR; metabolism; muscle; rapamycin; regeneration; somatic stem cell; trachea

PMID:
29220665
PMCID:
PMC5823264
DOI:
10.1016/j.stem.2017.11.008
[Indexed for MEDLINE]
Free PMC Article

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