Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells.

TitleAging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells.
Publication TypeJournal Article
Year of Publication2014
AuthorsRimmelé, P, Bigarella, CL, Liang, R, Izac, B, Dieguez-Gonzalez, R, Barbet, G, Donovan, M, Brugnara, C, Blander, JM, Sinclair, DA, Ghaffari, S
JournalStem Cell Reports
Volume3
Issue1
Pagination44-59
Date Published2014 Jul 08
KeywordsAnimals, Cell Aging, Cell Differentiation, Cell Lineage, Hematopoietic Stem Cells, Mice, Sirtuin 1, Stem Cells, Transcription Factors
Abstract

Aging hematopoietic stem cells (HSCs) exhibit defective lineage specification that is thought to be central to increased incidence of myeloid malignancies and compromised immune competence in the elderly. Mechanisms underlying these age-related defects remain largely unknown. We show that the deacetylase Sirtuin (SIRT)1 is required for homeostatic HSC maintenance. Differentiation of young SIRT1-deleted HSCs is skewed toward myeloid lineage associated with a significant decline in the lymphoid compartment, anemia, and altered expression of associated genes. Combined with HSC accumulation of damaged DNA and expression patterns of age-linked molecules, these have striking overlaps with aged HSCs. We further show that SIRT1 controls HSC homeostasis via the longevity transcription factor FOXO3. These findings suggest that SIRT1 is essential for HSC homeostasis and lineage specification. They also indicate that SIRT1 might contribute to delaying HSC aging.

DOI10.1016/j.stemcr.2014.04.015
Alternate JournalStem Cell Reports
PubMed ID25068121
PubMed Central IDPMC4110778
Grant ListT32 HD075735 / HD / NICHD NIH HHS / United States
T32 GM08553-13 / GM / NIGMS NIH HHS / United States
T32 GM008553 / GM / NIGMS NIH HHS / United States
R01 DK077174 / DK / NIDDK NIH HHS / United States
R01 HL116365 / HL / NHLBI NIH HHS / United States
R37 AG028730 / AG / NIA NIH HHS / United States
R01 RHL116365A / / PHS HHS / United States
R37 DK050107 / DK / NIDDK NIH HHS / United States