Aging and Clonal Behavior of Hematopoietic Stem Cells

Abstract

Hematopoietic stem cells (HSCs) are the only cell population that possesses both a self-renewing capacity and multipotency, and can give rise to all lineages of blood cells throughout an organism’s life. However, the self-renewal capacity of HSCs is not infinite, and cumulative evidence suggests that HSCs alter their function and become less active during organismal aging, leading ultimately to the disruption of hematopoietic homeostasis, such as anemia, perturbed immunity and increased propensity to hematological malignancies. Thus, understanding how HSCs alter their function during aging is a matter of critical importance to prevent or overcome these age-related changes in the blood system. Recent advances in clonal analysis have revealed the functional heterogeneity of murine HSC pools that is established upon development and skewed toward the clonal expansion of functionally poised HSCs during aging. In humans, next-generation sequencing has revealed age-related clonal hematopoiesis that originates from HSC subsets with acquired somatic mutations, and has highlighted it as a significant risk factor for hematological malignancies and cardiovascular diseases. In this review, we summarize the current fate-mapping strategies that are used to track and visualize HSC clonal behavior during development or after stress. We then review the age-related changes in HSCs that can be inherited by daughter cells and act as a cellular memory to form functionally distinct clones. Altogether, we link aging of the hematopoietic system to HSC clonal evolution and discuss how HSC clones with myeloid skewing and low regenerative potential can be expanded during aging.

Cellular enlargement - A new hallmark of aging?

“…A healthy blood system requires HSCs to balance and maintain both these abilities, which decline with age. This leads to stem cell exhaustion and biased lineage differentiation ( Yamashita and Iwama, 2022 ), which can contribute to the development of anemia, leukemia and a compromised immune system ( Dykstra and de Haan, 2008 ; Hill et al, 2017 ; Chen et al, 2019 ; Chopra and Bohlander, 2019 ; Anurogo et al, 2021 ).…”

Hematopoietic Stem Cells and the Immune System in Development and Aging

“…While the other part, under the influence of inflammatory stress and external and internal stimuli, begins to actively proliferate, which increases the risk of driver mutations accumulation that contribute to the selective advantage of some HSCs. The symmetrical propagation of HSC clones or the advantage in the asymmetric differentiation of one or more HSCs generates haematopoiesis clonality [ 17 , 130 , 156 ].…”

“…Thus, clonality is the result of several processes associated with aging: the accumulation of driver mutations that promote selective proliferation, epigenetic changes conferring selective advantages on the differentiation and/or proliferation of individual HSC, or HSPC further stimulated by age-dependent niche or autocrine inflammation (see Section 3.7 ) [ 17 , 170 ].…”

“…Given this focus, we do not discuss in detail other specialized aspects of hematopoietic development. We invite readers to refer to other recent, excellent reviews on specialized topics on HSC hematopoietic hierarchy, function, physiology, and aging [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ].…”

Immunosenescence, aging and successful aging

“…Bone marrow contains haematopoietic stem cells (HSCs) and non-HSCs. HSCs are multifunctional immature cell populations that possess self-renewing capacity and give rise to all blood cells of immune system ( 51 , 52 ). HSCs are decreased with aging and the senescent HSCs acquire increased DNA damage, dysfunctional function and myeloid bias, affecting the generation of naive T cells severely ( 53 , 54 ).…”