Concise review: hematopoietic stem cell aging, life span, and transplantation

Abstract

Self-renewal and multilineage differentiation of stem cells are keys to the lifelong homeostatic maintenance of tissues and organs. Hematopoietic aging, characterized by immunosenescence, proinflammation, and anemia, is attributed to age-associated changes in the number and function of hematopoietic stem cells (HSCs) and their microenvironmental niche. Genetic variants and factors regulating stem cell aging are correlatively or causatively associated with overall organismal aging and longevity. Translational use of HSCs for transplantation and gene therapy demands effective methods for stem cell expansion. Targeting the molecular pathways involved in HSC self-renewal, proliferation, and homing has led to enhanced expansion and engraftment of stem cells upon transplantation. HSC transplantation is less effective in elderly people, even though this is the demographic with the greatest need for this form of treatment. Thus, understanding the biological changes in the aging of stem cells as well as local and systematic environments will improve the efficacy of aged stem cells for regenerative medicine and ultimately facilitate improved health and life spans.

Figure 1.

Aging of the hematopoietic stem cells and their niche. Hematopoietic stem cells (HSCs) and their bone marrow microenvironmental niche undergo age-related changes because of a burden of genomic damage, telomere dysfunction, metabolic byproducts, and epigenetic shift during the aging process. At a young age, the composition of the HSC compartment, including myeloid-biased (My-bi) and lymphoid-biased (Ly-bi) HSC subpopulations, and their differentiation capacity are homeostatically maintained, enabling a balanced production of blood cells. In the old bone marrow, the HSC pool is expanded and My-bi HSCs become dominant over the Ly-bi population, resulting in a myeloid skewing at the expense of lymphocytes. Aging of the niche results in decreased homing and enhanced mobilization of old HSCs, thus demonstrating a reduced capacity to support HSC engraftment and differentiation in HSC transplantation. Note: analysis of the aging literature suggests that ages older than 60–65 are commonly called “the older population ” [–10, 67, 68, 82], even though “age” should be defined by the functional analysis and there is no general agreement on the definitive cutoff for “old age” [22].

Figure 2.

Effects of stem cell aging and rejuvenation on organismal longevity. During organismal aging, stem cells may undergo senescence or apoptosis, they may become tumorigenic, or they may retain their “youthful” state. Age-associated changes in the stem cell population underlie the increased disease incidence and decreased regenerative capacity in elderly people and ultimately produce negative effects on organismal longevity. In order to counteract such deleterious effects, stem cell-based gene therapy and regenerative medicine hold great promise in treating age-related degenerative and malignant diseases. These therapeutic strategies will, hopefully sooner rather than later, improve health span and life span in humans.