Hematopoietic stem cell aging: mechanism and consequence

Abstract

Advancing age is frequented by the onset of a variety of hematological conditions characterized by diminished homeostatic control of blood cell production. The fact that upstream hematopoietic stem and progenitor cells are obligate mediators of homeostatic control of all blood lineages, has implicated the involvement of these cells in the pathophysiology of these conditions. Indeed, evidence from our group and others has suggested that two of the most clinically significant age-associated hematological conditions, namely, the diminution of the adaptive immune system and the elevated incidence of myeloproliferative diseases, have their origin in cell autonomous changes in the functional capacity of hematopoietic stem cells.

Fig 1

Cell autonomous expansion of LT-HSC with age A) Schematic representation of the primitive hematopoietic compartment showing the lineage relationship and cell surface phenotype of long-term reconstituting hematopoietic stem cells (LT-HSC), and multi-potent progenitor cells. B) Representative FACS profiles of young, mid-aged, and old BM cells showing LT-HSC (red boxes) and multi-potent progenitor cell subsets (blue and green boxes). Cells were gated (boxes) through FSC-A vs. lineage, c-kit vs. Sca1, and flk2 vs. CD34 as shown. C) BM frequency of LT-HSC from young (n=5), middle-aged (n=5) and old mice (n=5) presented as a percent of the young animals. D) BM frequency of KLSflk2−CD34− side population cells young (n=5), and old mice (n=5) presented as a percent of the young animals. E) BM frequency of KLSCD34−Slamf1+ cells young (n=5), and old mice (n=5) presented as a percent of the young animals. Statistically significant (P < 0.05 by student's t-test) differences are indicated with asterisks. Double asterisks in B indicate statistical significance (P < 0.05) to both of the other age groups.

Fig 2

Lymphoid/myeloid lineage skewing of LT-HSC with age A) Representative flow cytometric profiles showing peripheral blood analysis of young recipient mice competitively transplanted with 50 LT-HSC (CD45.2) against 2x10⁵ competitor BM cells (CD45.1) from young (top panels) or old (bottom panels) donors showing total donor cell contribution (green contours, left panels), and contribution to B220+ B-cells (red contours, right panels) and Mac1+ myeloid cells (blue contours, right panels) 20 weeks post-transplant. The B220⁻, Mac1⁻ cells (purple contours) are TCRβ+ T-cells (not shown). Cells were pre-gated through FSC-A vs SSC, and Ter119 vs PI to exclude erythroid cells and dead cells. B) Representative flow cytometric profiles of committed myeloid progenitor cells from the BM of young and old mice showing common myeloid progenitors (CMP, blue contours), granulocyte-macrophage progenitors (GMP, purple contours) and megakaryocyte-erythroid progenitors (MEP, red contours). Cells were pre-gated through FSC-A vs. lineage (not shown). Representative flow cytometric profiles of flk2+ common lymphoid progenitors (CLP^flk2+, red contours) from the BM of young and old mice. Cells were pre-gated through FSC-A vs. lineage (not shown).

Fig 3

Model of hematopoietic stem cell aging A model for how the cellular and molecular changes accompanying hematopoietic stem cell aging contribute to clinically significant pathophysiological conditions of the aged hematopoietic system.