Extrinsic Factors of Aging and Hematopoiesis
المؤلف:
Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.
المصدر:
Hematology : Basic Principles and Practice
الجزء والصفحة:
8th E , P205
2025-11-26
73
Bone Marrow Microenvironment The spatial location where HSCs reside also has a significant impact on their activity. This microenvironment, termed a BM “niche,” is composed of a plethora of hematopoietic and non-hematopoietic cells such as mesenchymal stem cells, osteoblasts, endothelial cells, macrophages, among others. These supporting populations are able to regulate quiescence, self-renewal, proliferation, and differentiation of HSCs.
Collectively, niche cells regulate HSCs through the production of diverse cytokines, extracellular matrix proteins, and adhesion molecules. This raises the possibility that age-associated BM niche remodeling can influence the functioning of HSCs. Although recent studies have started to elucidate the mechanisms through which the niche regulates HSCs, limited data are available on the differences between young and aged HSC niches.
Classic BM transplantation showed that a young BM niche failed to rescue aging stem cell phenotypes when aged HSCs were transplanted into irradiated young recipients, suggesting that features observed upon HSC aging are mainly caused by intrinsic changes. However, young HSCs showed impaired homing and engraftment capability when trans planted into old recipients, while aged HSCs showed higher engraftment and less myeloid output when exposed to a young niche, suggesting a negative impact of the aged microenvironment on hematopoiesis. Importantly, a recent study showed that BM plasma cells increased in number with age and that the depletion of these cells reduced myeloid cell production in aged mice. In the future, greater effort is needed to investigate the roles of the BM niche in the context of HSC aging.
Senescence
Cellular senescence is another hallmark of aging, and the removal of senescent cells (SCs) can prevent or delay tissue dysfunction and extend the lifespan. It has been reported that the senolytic drug navitoclax (ABT263), a specific inhibitor of anti-apoptotic proteins, selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. ABT263 treatment also clears SCs in normally aged mice and improves the long-term engraftment potential of aged HSCs following serial transplantation. It is likely SCs impair BM HSC function due to the senescence-associated secretory phenotype (SASP), where inflammatory cytokines, such as interleukin 6 (IL-6), are secreted. The impact of inflammatory cytokines will be further discussed in the following section.
Inflammation
Inflammation is defined as a protective immune response, which underlies a variety of pathophysiological processes that are in part caused by infection and tissue injury/damage. HSCs are needed for multi-lineage differentiation to replenish immune effector cells consumed during inflammation. Actually, HSCs can also directly sense inflammatory signals since a broad spectrum of inflammatory cytokine/chemokine receptors are expressed by HSCs, directly influencing HSC fate decisions. It has been shown that HSCs are activated and produce more myeloid cells but fewer lymphoid cells in response to inflammation. Many studies have demonstrated that signaling via inflammatory cytokines impacts long-term HSC potential.
In an aging context, the role of inflammation is more prominent. Chronic inflammation occurs frequently in the elderly and is associated with multiple age-related diseases—referred to as “inflammaging.” Age-related functional alterations (such as impaired repopulation potential and myeloid bias) of HSCs are very reminiscent of those seen under inflammatory stresses. Moreover, aged HSCs demonstrate increased myeloid output in response to inflammatory challenges as compared to young HSCs. Elevated levels of the pro inflammatory CC-chemokine ligand 5 (CCL5) have been reported in the old BM niche, which is likely responsible for myeloid skewing of aged HSCs. Furthermore, it has been shown that tumor necrosis factor α (TNF-α) can drive myeloid regeneration, and the treatment of aged mice with interleukin 1 (IL-1) and TNF-α inhibitors reduces myelopoiesis. Interestingly, an HSC-specific TNF-α signature is enriched in aged and malignant HSCs, supporting the idea that inflammation plays an important role in HSC aging. To note, positive feedback between aging and inflammation may exist, as more myeloid cells, which secrete pro-inflammatory cytokines, are produced as HSCs age. As a consequence, those cytokines in turn promote myelopoiesis which then promotes HSC aging.
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