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.
Highlights
Hematopoietic stem cells (HSCs) are blood-forming stem cells that can clonally expand by self-renewing cell division, and that disseminate their clonal progeny by differentiating to all lineages of the blood and immune cells, such as leukocytes, erythrocytes and platelets [1]
There is still a debate, in particular with regard to the labeling efficiency of HSCs in this system [38], these observations point out that while HSCs actively contribute to hematopoiesis upon the transplantation that inevitably accompanies various hematopoietic stresses, non-self-renewing multipotent progenitors could be a main source of native, unperturbed hematopoiesis where such stress does not exist, arguing against the dogma of “bona fide” HSCs that had long been defined by transplantation experiments
The recent progress in single-cell analysis and fate mapping tools allows researchers to track the behavioral history of individual HSC clones in vivo
Summary
Hematopoietic stem cells (HSCs) are blood-forming stem cells that can clonally expand by self-renewing cell division, and that disseminate their clonal progeny by differentiating to all lineages of the blood and immune cells, such as leukocytes, erythrocytes and platelets [1]. Some exceptions have been identified recently, such as tissueresident macrophages [2,3] and innate-like B and T lymphocytes [4], HSCs are an important source for the vast majority of the blood and immune cells throughout an organism’s life, during steady-state hematopoiesis and hematopoietic regeneration after injury, being attractive targets for preventing or curing hematopoietic disorders. Even after the establishment and sophistication of efficient HSC purification methods, single-cell-based analyses have revealed a remarkable phenotypic and functional heterogeneity in the HSC pool [5]. Recent advances in the clonal tracking methods, referred to as “fate mapping”, provided evidence that HSC heterogeneity can originate from individual clones that emerge during the developmental process [6,7]. Clonal analyses have revealed an agerelated expansion of functionally skewed HSCs, which is associated with an imbalanced production between blood lineages, and reduced clonal diversity in hematopoiesis [6,8,9]. We will summarize the current understanding of HSC clonal behavior, since they emerge until the end of life, and discuss possible mechanisms that underlie functional diversity and age-dependent alteration in HSC clones
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