Stem cells and the aging hematopoietic system

Abstract

Advancing age is accompanied by a number of clinically significant conditions arising in the hematopoietic system that include: diminution and decreased competence of the adaptive immune system, elevated incidence of certain autoimmune diseases, increased hematological malignancies, and elevated incidence of age-associated anemia. As with most tissues, the aged hematopoietic system also exhibits a reduced capacity to regenerate and return to normal homeostasis after injury or stress. Evidence suggests age-dependent functional alterations within the hematopoietic stem cell compartment significantly contribute to many of these pathophysiologies. Recent developments have shed light on how aging of the hematopoietic stem cell compartment contributes to hematopoietic decline through diverse mechanisms.

Figure 1

In vivo reconstitution potential and lineage potential of young and old HSCs. 500 HSCs (LSKCD34⁻Flk2⁻) were isolated from 3 month-old CD45.1 or 24 month-old CD45.2 mice and injected in lethally irradiated CD45.1/CD45.2 (F1) mice along with a radioprotective dose of 300,000 F1 Sca-1-depleted bone marrow cells. Representative peripheral bleed data (17 weeks post-transplant) illustrate the point that HSCs from old mice exhibit a lower total reconstitution potential. Also, in the same microenvironment, HSCs from young donors yield lineage-balanced reconstitution, while a myeloid bias and reduced lymphoid reconstitution is observed from the stem cells of old donors.

Figure 2

Human hematopoietic stem cell frequency increases with age. (a) Identification of hematopoietic stem cells (Lineage⁻CD90⁺CD38⁻CD34⁺) from a representative human bone marrow aspirate. Nineteen consented individuals ranging in age from 19 to 84 donated bone marrow aspirates for this study. Bone marrow mononuclear cells were first gated on size (FSC-A) and granularity (SSC-A), followed by doublet discrimination, lineage negativity (negative staining for a cocktail of antibodies against antigens found on differentiated blood cells including glycophorin A, CD11b, CD2, CD3, CD16, CD19, CD20, CD14, and CD56), and viability (propidium iodide (PI) negative). Finally, CD90 positive cells were gated for CD34 positivity and CD38 negativity. (b) Bone marrow frequency of HSCs (Lineage⁻CD90⁺CD38⁻CD34⁺) bone marrow mononuclear cells plotted against donor age with Pearson correlation (r) and p-value (P) shown. Of note, analysis of bone marrow mononuclear cells indicate that a significant fraction of CD34⁺ cells stain positively for lineage markers and CD38 positive (not shown) stressing the importance of using a comprehensive marker panel when evaluating stem and progenitor cell populations.

Figure 3

Model of aging in the hematopoietic stem and progenitor cell compartment and impact on the aging hematopoietic system. Schematic representation of hematopoietic differentiation from hematopoietic stem cells (HSCs) through multipotent progenitors (MPPFlk2⁻, MPPFlk2^low) lymphoid-primed multi-potent progenitors (LMPP), common lymphoid progenitors (CLP), common myeloid progenitor progenitors (CMP), megakaryocyte-erythrocyte progenitors (MEP), and granulocyte-monocyte progenitors (GMP), onto mature effector cells during aging, and proposed impact on the aged hematopoietic system. Steady state frequencies of stem and progenitor cells have been reported [–13].