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

Pauline Rimmelé; Carolina L. Bigarella; Raymond Liang; Brigitte Izac; Rebeca Dieguez-Gonzalez; Gaetan Barbet; Michael Donovan; Carlo Brugnara; Julie M. Blander; David A. Sinclair; Saghi Ghaffari

doi:10.1016/j.stemcr.2014.04.015

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

Pauline Rimmelé, Carolina L. Bigarella, Raymond Liang, Brigitte Izac, Rebeca Dieguez-Gonzalez, Gaetan Barbet, Michael Donovan, Carlo Brugnara, Julie M. Blander, David A. Sinclair, Saghi Ghaffari

Research output: Contribution to journal › Article › peer-review

113 Scopus citations

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.

Original language	English (US)
Pages (from-to)	44-59
Number of pages	16
Journal	Stem Cell Reports
Volume	3
Issue number	1
DOIs	https://doi.org/10.1016/j.stemcr.2014.04.015
State	Published - Jul 8 2014
Externally published	Yes

All Science Journal Classification (ASJC) codes

Biochemistry
Genetics
Developmental Biology
Cell Biology

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10.1016/j.stemcr.2014.04.015

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title = "Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells",

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.",

author = "Pauline Rimmel{\'e} and Bigarella, {Carolina L.} and Raymond Liang and Brigitte Izac and Rebeca Dieguez-Gonzalez and Gaetan Barbet and Michael Donovan and Carlo Brugnara and Blander, {Julie M.} and Sinclair, {David A.} and Saghi Ghaffari",

note = "Funding Information: We thank Valentina D{\textquoteright}Escamard for her technical help, Dr. Kateri Moore (Mount Sinai) for critically reading the manuscript, and The Flow Cytometry Shared Research Facility and the Histology Facility at Icahn School of Medicine at Mount Sinai. B.I. was partially supported by Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale, and R.D.-G. was supported by the Spanish Instituto de Salud Carlos III (Sara Borrell CD09/00014). R.L. was partially supported by grants from the NIH (T32 GM08553-13 and T32 HD075735). This work was supported in part by NIH grants (RO1 DK077174 and RO1 RHL116365A; S.G., Co-PI), a New York State Stem Cell Science (NYSTEM) award (CO24408), a Myeloproliferative Neoplasm Foundation (MPN) award and an Irma Hirschl/Weill-Caulier Trust Research award to S.G. ",

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doi = "10.1016/j.stemcr.2014.04.015",

language = "English (US)",

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T1 - Aging-like phenotype and defective lineage specification in SIRT1-deleted hematopoietic stem and progenitor cells

AU - Rimmelé, Pauline

AU - Bigarella, Carolina L.

AU - Liang, Raymond

AU - Izac, Brigitte

AU - Dieguez-Gonzalez, Rebeca

AU - Barbet, Gaetan

AU - Donovan, Michael

AU - Brugnara, Carlo

AU - Blander, Julie M.

AU - Sinclair, David A.

AU - Ghaffari, Saghi

N1 - Funding Information: We thank Valentina D’Escamard for her technical help, Dr. Kateri Moore (Mount Sinai) for critically reading the manuscript, and The Flow Cytometry Shared Research Facility and the Histology Facility at Icahn School of Medicine at Mount Sinai. B.I. was partially supported by Institut National de la Santé et de la Recherche Médicale, and R.D.-G. was supported by the Spanish Instituto de Salud Carlos III (Sara Borrell CD09/00014). R.L. was partially supported by grants from the NIH (T32 GM08553-13 and T32 HD075735). This work was supported in part by NIH grants (RO1 DK077174 and RO1 RHL116365A; S.G., Co-PI), a New York State Stem Cell Science (NYSTEM) award (CO24408), a Myeloproliferative Neoplasm Foundation (MPN) award and an Irma Hirschl/Weill-Caulier Trust Research award to S.G.

PY - 2014/7/8

Y1 - 2014/7/8

N2 - 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.

AB - 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.

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ER -

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

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