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. Issue 3 (3rd March 2019)

• Record Type: Journal Article
• Authors: Gnani, Daniela; Crippa, Stefania; della Volpe, Lucrezia; Rossella, Valeria; Conti, Anastasia; Lettera, Emanuele; Rivis, Silvia; Ometti, Marco; Fraschini, Gianfranco; Bernardo, Maria Ester; Di Micco, Raffaella
• Is Part Of: Aging cell. Volume 18:Issue 3(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-03-03
• Subjects: aging -- DNA damage -- hematopoietic stem and progenitor cells -- inflammation -- mesenchymal stromal cells -- SASP -- senescence; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.12933
• Languages: English
• ISSNs: 1474-9718

Abstract

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. Abstract : Aged mesenchymal stromal cells (MSC) display early senescence features including SA‐β‐Gal accumulation, DDR, and SASP activation. Through SASP, aged MSC impair the clonogenic potential of hematopoietic stem and progenitor cells (HSPC) and induce the activation of a pro‐inflammatory transcriptional program in young HSPC.