Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency.
HSC
dormancy
fission
hematopoietic stem cell
label retention
lysosomes
mTOR
mitochondria
mitophagy
quiescence
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
05 03 2020
05 03 2020
Historique:
received:
27
02
2019
revised:
17
10
2019
accepted:
17
01
2020
pubmed:
29
2
2020
medline:
28
4
2021
entrez:
29
2
2020
Statut:
ppublish
Résumé
Quiescence is a fundamental property that maintains hematopoietic stem cell (HSC) potency throughout life. Quiescent HSCs are thought to rely on glycolysis for their energy, but the overall metabolic properties of HSCs remain elusive. Using combined approaches, including single-cell RNA sequencing (RNA-seq), we show that mitochondrial membrane potential (MMP) distinguishes quiescent from cycling-primed HSCs. We found that primed, but not quiescent, HSCs relied readily on glycolysis. Notably, in vivo inhibition of glycolysis enhanced the competitive repopulation ability of primed HSCs. We further show that HSC quiescence is maintained by an abundance of large lysosomes. Repression of lysosomal activation in HSCs led to further enlargement of lysosomes while suppressing glucose uptake. This also induced increased lysosomal sequestration of mitochondria and enhanced the competitive repopulation ability of primed HSCs by over 90-fold in vivo. These findings show that restraining lysosomal activity preserves HSC quiescence and potency and may be therapeutically relevant.
Identifiants
pubmed: 32109377
pii: S1934-5909(20)30013-8
doi: 10.1016/j.stem.2020.01.013
pmc: PMC8075247
mid: NIHMS1569124
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
359-376.e7Subventions
Organisme : NCI NIH HHS
ID : R01 CA205975
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136255
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD075735
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests Some elements of this work have been filed in a patent application to the United States Patent and Trademark Office. R.L. is currently employed by HemoGenix.
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