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

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.

Leydig‐like cells derived from reprogrammed human foreskin fibroblasts by CRISPR/dCas9 increase the level of serum testosterone in castrated male rats

“…As the transplant time lengthened, the serum testosterone level of the iLCs group increased gradually and reached its peak (2.2 ng/mL) 3 weeks after implantation but gradually declined over 3 weeks later. Regarding this phenomenon, there may be many factors involved, such as off‐target effects despite low probability, the senescence of implanted cells caused by adverse factors in vivo, inflammatory reactions and so on, that eventually led to the observed result . The trend of serum testosterone levels after iLCs transplantation was similar to our previous study in vitro .…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…Moreover, Liu et al [118] demonstrated that the loss of osteogenic potential in aged BM-MSCs is mediated by p53 increase through the miR-17 pathway. MSC aging was also correlated to impaired hematopoietic functions: BM-MSCs (fundamental for the maintenance of the hematopoietic stem cell compartment in the bone marrow) from aged donors were shown to activate a SASP-like program contributing to young HSCs functional impairment by promoting an inflammatory state in HSCs [119]. Senescence of synovial and subchondral BM-MSCs is likely to contribute to joint alteration and osteoarthritis (OA) development: this was shown in vitro and in vivo with p16-positive human MSCs co-cultured with OA chondrocytes or intra-articularly injected in young mice [120].…”

Restoring aged stem cell functionality: Current progress and future directions

“…42 MSCs are known to modulate their tissue micro-environment through their highly diverse secretomic profiles, 43,44 which are drastically altered with age. [45][46][47] As a result, the secretomes from aged bone-marrow derived MSCs have decreased immune-modulatory properties and can impede HSC differentiation and proliferation. 46…”

“…[45][46][47] As a result, the secretomes from aged bone-marrow derived MSCs have decreased immune-modulatory properties and can impede HSC differentiation and proliferation. 46…”