p16INK4A-dependent senescence in the bone marrow niche drives age-related metabolic changes of hematopoietic progenitors

Abstract

Rapid and effective leucocyte response to infection is a fundamental function of the bone marrow (BM). However, with increasing age this response becomes impaired, resulting in an increased burden of infectious diseases. Here, we investigate how aging changes the metabolism and function of hematopoietic progenitor cells (HPCs) and the impact of the bone marrow niche on this phenotype. We found that, in response to LPS induced stress, HPC mitochondrial function is impaired and there is a failure to upregulate the TCA cycle in progenitor populations in aged animals compared to young animals. Furthermore, aged mesenchymal stromal cells (MSC) of the BM niche, but not HPCs, exhibit a senescent phenotype and selective depletion of senescent cells from the BM niche, as well as treatment with the senolytic drug ABT-263, improves mitochondrial function of HPCs when stressed with LPS. In summary, age related HPC metabolic dysfunction occurs indirectly as a 'bystander phenomenon' in the aging BM niche and can be restored by targeting senescent MSCs.

Unraveling Heterogeneity in the Aging Hematopoietic Stem Cell Compartment: An Insight From Single-cell Approaches

“…A recent study demonstrated impaired mitochondrial function in aged HSPCs when stressed with LPSs 73 . HSPC malfunction during stress was supported by the accumulation of senescent, p16 INK4A‐ positive MSCs that naturally occur with aging in the bone marrow.…”

“…In turn, mitochondrial impairment in HSPCs could be improved by senolytic depletion of bone marrow-resident senescent mesenchymal stromal cells, highlighting the close interplay between aging HSCs and their niche. 73 As mentioned above, the detection of senescence is well established via various SA-ß gal substrates or p16 INK4A levels by flow cytometry and can readily be used to detect and isolate senescent MSCs. 74 Another recent study characterizing alterations in the bone marrow niche highlighted a role of the middle-aged bone marrow in driving HSC aging due to decreasing levels of insulin-like growth factor 1 (IGF1).…”

“…71,72 A recent study demonstrated impaired mitochondrial function in aged HSPCs when stressed with LPSs. 73 HSPC malfunction during stress was supported by the accumulation of senescent, p16 INK4Apositive MSCs that naturally occur with aging in the bone marrow. In turn, mitochondrial impairment in HSPCs could be improved by senolytic depletion of bone marrow-resident senescent mesenchymal stromal cells, highlighting the close interplay between aging HSCs and their niche.…”

“…HSPC malfunction during stress was supported by the accumulation of senescent, p16 INK4A‐ positive MSCs that naturally occur with aging in the bone marrow. In turn, mitochondrial impairment in HSPCs could be improved by senolytic depletion of bone marrow‐resident senescent mesenchymal stromal cells, highlighting the close interplay between aging HSCs and their niche 73 . As mentioned above, the detection of senescence is well established via various SA‐ß gal substrates or p16 INK4A levels by flow cytometry and can readily be used to detect and isolate senescent MSCs 74 …”

Clonal hematopoiesis and its impact on the aging osteo-hematopoietic niche

“…Besides the irreversible cell cycle arrest that senescent cells undergo, they also produce factors involved in matrix remodeling, pro-angiogenic factors, growth factors, and a wide variety of proinflammatory factors collectively termed senescence-associated secretory phenotype (SASP) [ 76 ]. A recent study in mice showed that by selectively depleting senescent MSCs or by systemic treatment with a senolytic drug, the metabolic fitness of HSCs, in particular in response to bacterial stimuli, could be improved [ 80 ]. Furthermore, increased senescence of MSCs has been observed in mice lacking Wnt signaling within the BM microenvironment, along with impaired endosteal niche and bone mass accrual, and age-dependent attenuated HSC repopulation activity and myeloid skewing [ 81 ].…”