Endothelial mTOR maintains hematopoiesis during aging.
Aging
/ physiology
Animals
Bone Marrow Cells
/ cytology
Cellular Microenvironment
Endothelial Cells
/ metabolism
Hematopoiesis
/ drug effects
Hematopoietic Stem Cells
/ cytology
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Mechanistic Target of Rapamycin Complex 2
/ metabolism
Mice, Inbred C57BL
Mice, Transgenic
Signal Transduction
Sirolimus
/ pharmacology
TOR Serine-Threonine Kinases
/ metabolism
Transcription, Genetic
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 06 2020
01 06 2020
Historique:
received:
02
07
2019
revised:
18
12
2019
accepted:
13
03
2020
entrez:
15
4
2020
pubmed:
15
4
2020
medline:
17
2
2021
Statut:
ppublish
Résumé
Aging leads to a decline in hematopoietic stem and progenitor cell (HSPC) function. We recently discovered that aging of bone marrow endothelial cells (BMECs) leads to an altered crosstalk between the BMEC niche and HSPCs, which instructs young HSPCs to behave as aged HSPCs. Here, we demonstrate aging leads to a decrease in mTOR signaling within BMECs that potentially underlies the age-related impairment of their niche activity. Our findings reveal that pharmacological inhibition of mTOR using Rapamycin has deleterious effects on hematopoiesis. To formally determine whether endothelial-specific inhibition of mTOR can influence hematopoietic aging, we conditionally deleted mTOR in ECs (mTOR(ECKO)) of young mice and observed that their HSPCs displayed attributes of an aged hematopoietic system. Transcriptional profiling of HSPCs from mTOR(ECKO) mice revealed that their transcriptome resembled aged HSPCs. Notably, during serial transplantations, exposure of wild-type HSPCs to an mTOR(ECKO) microenvironment was sufficient to recapitulate aging-associated phenotypes, confirming the instructive role of EC-derived signals in governing HSPC aging.
Identifiants
pubmed: 32289154
pii: 151661
doi: 10.1084/jem.20191212
pmc: PMC7971143
pii:
doi:
Substances chimiques
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Mechanistic Target of Rapamycin Complex 2
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Sirolimus
W36ZG6FT64
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
Subventions
Organisme : NIA NIH HHS
ID : R01 AG065436
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204308
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL133021
Pays : United States
Informations de copyright
© 2020 Ramalingam et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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