Title | Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Rimmelé, P, Bigarella, CL, Liang, R, Izac, B, Dieguez-Gonzalez, R, Barbet, G, Donovan, M, Brugnara, C, Blander, JM, Sinclair, DA, Ghaffari, S |
Journal | Stem Cell Reports |
Volume | 3 |
Issue | 1 |
Pagination | 44-59 |
Date Published | 2014 Jul 08 |
Keywords | Animals, 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. |
DOI | 10.1016/j.stemcr.2014.04.015 |
Alternate Journal | Stem Cell Reports |
PubMed ID | 25068121 |
PubMed Central ID | PMC4110778 |
Grant List | T32 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 |