Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal.
Animals
Autophagy
/ drug effects
Cell Differentiation
/ drug effects
Cell Self Renewal
/ drug effects
Cell Survival
/ drug effects
Endoplasmic Reticulum Stress
/ drug effects
Fatty Acid Desaturases
/ antagonists & inhibitors
Female
Fenretinide
/ pharmacology
Gene Expression Regulation
/ genetics
Gene Knockdown Techniques
Hematopoietic Stem Cells
/ enzymology
Humans
Male
Mass Spectrometry
Mice
Mice, Inbred NOD
Proteostasis
/ drug effects
RNA, Small Interfering
RNA-Seq
Single-Cell Analysis
Sphingolipids
/ chemistry
Transplantation, Heterologous
DEGS1
StemRegenin-1
UM171
autophagy
fenretinide
hematopoietic stem cell
lipidomics
sphingolipid metabolism
umbilical cord blood
unfolded protein response
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
07 11 2019
07 11 2019
Historique:
received:
18
01
2019
revised:
09
07
2019
accepted:
23
09
2019
pubmed:
22
10
2019
medline:
10
9
2020
entrez:
22
10
2019
Statut:
ppublish
Résumé
Cellular stress responses serve as crucial decision points balancing persistence or culling of hematopoietic stem cells (HSCs) for lifelong blood production. Although strong stressors cull HSCs, the linkage between stress programs and self-renewal properties that underlie human HSC maintenance remains unknown, particularly at quiescence exit when HSCs must also dynamically shift metabolic state. Here, we demonstrate distinct wiring of the sphingolipidome across the human hematopoietic hierarchy and find that genetic or pharmacologic modulation of the sphingolipid enzyme DEGS1 regulates lineage differentiation. Inhibition of DEGS1 in hematopoietic stem and progenitor cells during the transition from quiescence to cellular activation with N-(4-hydroxyphenyl) retinamide activates coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs to maintain immunophenotypic and functional HSCs. Thus, our work identifies a linkage between sphingolipid metabolism, proteostatic quality control systems, and HSC self-renewal and provides therapeutic targets for improving HSC-based cellular therapeutics.
Identifiants
pubmed: 31631013
pii: S1934-5909(19)30393-5
doi: 10.1016/j.stem.2019.09.008
pmc: PMC6838675
pii:
doi:
Substances chimiques
RNA, Small Interfering
0
Sphingolipids
0
Fenretinide
187EJ7QEXL
Fatty Acid Desaturases
EC 1.14.19.-
DEGS1 protein, human
EC 1.14.99.-
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
639-653.e7Subventions
Organisme : Medical Research Council
ID : MC_PC_12009
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : P01 CA097132
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009979
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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