Age-related changes in human hematopoietic stem/progenitor cells

Abstract

Adult stem cells are critical for maintaining cellular homeostasis throughout life, yet the effects of age on their regenerative capacity are poorly understood. All lymphoid and myeloid blood cell lineages are continuously generated from hematopoietic stem cells present in human bone marrow. With age, significant changes in the function and composition of mature blood cells are observed. In this study, we report that age-related changes also occur in the human hematopoietic stem cell compartment. We find that the proportion of multipotent CD34(+) CD38(-) cells increases in the bone marrow of elderly (>70 years) individuals. CD34(+) CD38(+) CD90(-) CD45RA(+/-) CD10(-) and CD34(+) CD33(+) myeloid progenitors persist at the same level in the bone marrow, while the frequency of early CD34(+) CD38(+) CD90(-) CD45RA(+) CD10(+) and committed CD34(+) CD19(+) B-lymphoid progenitors decreases with age. In contrast to mice models of aging, transplantation experiments with immunodeficient NOD/SCID/IL-2Rγ null (NSG) mice showed that the frequency of NSG repopulating cells does not change significantly with age, and there is a decrease in myeloid lineage reconstitution. An age-related decrease in the capacity of CD34(+) cells to generate myeloid cells was also seen in colony-forming assays in vitro. Thus, with increasing age, human hematopoietic stem/progenitor cells undergo quantitative changes as well as functional modifications.

Dynamics of Human Prothymocytes and Xenogeneic Thymopoiesis in Hematopoietic Stem Cell-Engrafted Nonobese Diabetic-SCID/IL-2rγnull Mice

“…An even more severe phenotype is observed in 2-mo-old mice grafted with CD34 + HPCs from ABM that produce only limited numbers of prothymocytes expressing dramatically reduced CD7 levels, and exhibit only marginal thymopoietic activity. In line with a report showing an abnormal expansion in elderly people (30), increased numbers of CD34 ++ CD38 lo HPCs are also noted in the BM of ABM mice at 1 mo after graft. Finally, consistent with their limited BM engraftment, ABM CD34 + HPCs finally prove unable to maintain stable xenogeneic BM hematopoiesis beyond 1 mo after graft.…”

Human and murine hematopoietic stem cell aging is associated with functional impairments and intrinsic megakaryocytic/erythroid bias

“…In addition, donor age affects outcome of clinical BM transplantations, although this most likely cannot be solely attributed to reduced HSC performance [25][26][27][28][29]. More direct evaluations of the frequencies and function of aged human hematopoietic stem and progenitor cells (HSPCs) from a limited number of individuals displayed similarities to previous findings in the mouse, including an increased myeloid-to-lymphoid output ratio and decreased reconstitution potential [30], although this is not undisputed [31].…”

“…In this study, we characterized the aging process within the most primitive compartments of human hematopoiesis, and revealed prominent alterations in between CB to adult and advanced aged BM (Figs 1 and 2). For comparison, we conducted similar analyses in aging murine BM, hypothesizing that conserved themes of human and murine hematopoietic aging might be of evolutional importance and because of the seemingly conflicting data that have been reported in both human [30,31] and murine [11-15, 18, 21] HSPC aging.…”

Feasibility of marrow harvesting from pediatric sibling donors without hematopoietic growth factors and allotransfusion

“…We also showed that younger donors yielded higher concentrations of CD34 + cells (Figure 2b). Age-related changes in human hematopoietic stem/ progenitor cells have been reported, 10 as has the lack of an association in adults between age and any progenitor cell subtype in BM. 11 However, the effect of aging on human hematopoietic stem cells in BM has not been sufficiently analyzed in children.…”