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An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program.
- Source :
-
Aging cell [Aging Cell] 2019 Jun; Vol. 18 (3), pp. e12933. Date of Electronic Publication: 2019 Mar 03. - Publication Year :
- 2019
-
Abstract
- Hematopoietic stem and progenitor cells (HSPC) reside in the bone marrow (BM) niche and serve as a reservoir for mature blood cells throughout life. Aging in the BM is characterized by low-grade chronic inflammation that could contribute to the reduced functionality of aged HSPC. Mesenchymal stromal cells (MSC) in the BM support HSPC self-renewal. However, changes in MSC function with age and the crosstalk between MSC and HSPC remain understudied. Here, we conducted an extensive characterization of senescence features in BM-derived MSC from young and aged healthy donors. Aged MSC displayed an enlarged senescent-like morphology, a delayed clonogenic potential and reduced proliferation ability when compared to younger counterparts. Of note, the observed proliferation delay was associated with increased levels of SA-β-galactosidase (SA-β-Gal) and lipofuscin in aged MSC at early passages and a modest but consistent accumulation of physical DNA damage and DNA damage response (DDR) activation. Consistent with the establishment of a senescence-like state in aged MSC, we detected an increase in pro-inflammatory senescence-associated secretory phenotype (SASP) factors, both at the transcript and protein levels. Conversely, the immunomodulatory properties of aged MSC were significantly reduced. Importantly, exposure of young HSPC to factors secreted by aged MSC induced pro-inflammatory genes in HSPC and impaired HSPC clonogenic potential in a SASP-dependent manner. Altogether, our results reveal that BM-derived MSC from aged healthy donors display features of senescence and that, during aging, MSC-associated secretomes contribute to activate an inflammatory transcriptional program in HSPC that may ultimately impair their functionality.<br /> (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)
- Subjects :
- Adolescent
Adult
Aged
Cell Proliferation physiology
Cells, Cultured
Cellular Senescence drug effects
Cellular Senescence physiology
Colony-Forming Units Assay
Cytokines genetics
DNA Damage genetics
DNA Damage physiology
Flow Cytometry
Hematopoietic Stem Cells immunology
Humans
Inflammation metabolism
Lipofuscin metabolism
Mesenchymal Stem Cells immunology
Mesenchymal Stem Cells physiology
Reactive Oxygen Species metabolism
Young Adult
beta-Galactosidase metabolism
Cellular Senescence immunology
Cytokines metabolism
Hematopoietic Stem Cells metabolism
Inflammation immunology
Mesenchymal Stem Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1474-9726
- Volume :
- 18
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Aging cell
- Publication Type :
- Academic Journal
- Accession number :
- 30828977
- Full Text :
- https://doi.org/10.1111/acel.12933