A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells - PubMed (original) (raw)

A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells

Rebecca H Cho et al. Blood. 2008.

Abstract

Whether hematopoietic stem cells (HSCs) change with aging has been controversial. Previously, we showed that the HSC compartment in young mice consists of distinct subsets, each with predetermined self-renewal and differentiation behavior. Three classes of HSCs can be distinguished based on their differentiation programs: lymphoid biased, balanced, and myeloid biased. We now show that aging causes a marked shift in the representation of these HSC subsets. A clonal analysis of repopulating HSCs demonstrates that lymphoid-biased HSCs are lost and long-lived myeloid-biased HSCs accumulate in the aged. Myeloid-biased HSCs from young and aged sources behave similarly in all aspects tested. This indicates that aging does not change individual HSCs. Rather, aging changes the clonal composition of the HSC compartment. We show further that genetic factors contribute to the age-related changes of the HSC subsets. In comparison with B6 mice, aged D2 mice show a more pronounced shift toward myeloid-biased HSCs with a corresponding reduction in the number of both T- and B-cell precursors. This suggests that low levels of lymphocytes in the blood can be a marker for HSC aging. The loss of lymphoid-biased HSCs may contribute to the impaired immune response to infectious diseases and cancers in the aged.

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Figures

Figure 1

Figure 1

Increased number of myeloid cells in the blood of aged D2. The percentage of myeloid cells (■), and B (□) and T (formula image) lymphocytes in blood was measured from young (A-C) and aged (D-F) mice on the B6 (A,D), B/c (B,E), and D2 (C,F) background. Each bar represents the measurements from an individual mouse. The age of each mouse is indicated on the x-axis. Data are normalized to 100% to facilitate comparison. The mean L/M ratio and standard deviation for each group is shown in panel G. An * indicates that L/M ratios were significantly different from those obtained for aged D2 mice.

Figure 2

Figure 2

Relative repopulation units and differentiation potential of HSCs from aged mice. (A) Relative competitive repopulating units (rXRUs) in aged D2 are lower than in young D2 or aged B6 mice. Four mice were injected with 5 × 105 BM cells in each group. All mice received an equal dose of competitor marrow. Horizontal stripes indicate aged B6-CD45.1 plus young B6; diagonal stripes, aged D2-CD45.1 plus young D2; and vertical stripes, young D2-CD45.1 plus young D2. Donor-type cells (CD45.1) in blood were enumerated 5 months later, and the number of rXRUs per 105 cells were calculated as described. (B) Lineage contribution of HSCs in competitive repopulation: Shown is the percentage of myeloid cells (■), B lymphocytes (□), and T lymphocytes (▩) of donor origin for each mouse in each group. The mice are from the experiment described in panel A. The mean L/M ratio (± SD) for each group is indicated. The difference between the L/M ratios of aged and young D2 (P = .008) is significant; the difference between aged D2 and aged B6 (P = .06) approaches significance. (C) Lineage in noncompetitive repopulation. Mice received 105 Lin− cells from aged B6 or D2 donors (noncompetitive). Each bar represents a different experiment with a different donor. The difference between the L/M ratios of D2 versus B6 mice is significant with P = .051.

Figure 3

Figure 3

Aging changes the composition of the HSC compartment. The percentage of HSC clones that had Bala (formula image), My-bi (■), or Ly-bi (□) differentiation potential from young and aged animals is shown for B6 (A) and D2 (B). The number of individual HSC clones that was evaluated for each source of HSCs is indicated at the x-axis.

Figure 4

Figure 4

The repopulation capacity of HSC clones from young versus aged and in B6 versus D2 mice is similar. AUC values were calculated for each individual repopulation kinetic for the first 7 months after transplantation. These values were sorted into bins using increments of 50. Shown are the percentages of HSCs that fall into each of these bins for young B6 (46 clones), aged B6 (29), young D2 (34), and aged D2 (24) HSCs. This analysis includes only clones where 1, 3, 5, and 7 months of data were available. Not all clones analyzed in Figure 3 were analyzed at these time points.

Figure 5

Figure 5

The number of colony-forming units thymus are reduced in aged D2 but not in B6 mice. Shown is the frequency of CFUt per 105 cells injected in B6 (left panel, mean and SD of 3 experiments) and D2 mice (right panel, 1 experiment using 20 hosts). Animals were injected with mixtures of young (y) and aged (a) BM with an excess of host-type BM. CFUt frequencies were calculated from the number of mice that had thymic donor-type cells derived from either the aged or the young donors at 4 weeks. For details, see “Colony-forming unit thymus assay.”

Figure 6

Figure 6

Blunted IL-7 response of pro-B cells derived from young and aged My-bi HSCs. BM cells from young (A) or aged (B) D2 or B6 mice were cultured in 10 ng/mL IL-7 for 1 week. BM cells from hosts, clonally repopulated by individual My-bi HSCs (C), were cultured in the same way. The data are expressed as mean percentage recovery of donor-type cells after culture (± SD). The number (n) of independent experiments performed is indicated at the bottom.

Figure 7

Figure 7

Clonal competition and obscuration. A My-bi (□) and a Ly-bi (●) HSC clone from young B6 donors were identified in primary hosts by their lineage contribution. BM cells (5 × 106) from the primary hosts were then injected into secondary hosts either alone (A,C) or as an equal mixture (B,D,E). Repopulation levels were measured at the indicated time points after transplantation into the secondary host. The HSC clones were originally obtained from a B6-GFP and a B6-CD45.1 donor, respectively, and the progenies of the clones were readily distinguishable. (A) Percentage donor-type cells in 2 mice each that received either the My-bi or the Ly-bi HSCs. (B) Percentage donor-type cells in 4 mice that received a 1:1 mixture of the My-bi and the Ly-bi HSCs. (C-E) The level of myeloid cells (■), B cells (□), and T cells (▩) in the donor-type cells at 7 months after transplantation except for mouse mix 8, where 5 months of data are presented. (C) Lineage contribution in mice that received either My-bi or Ly-bi HSCs. L1, L2, and M1 and M2 in panel C are the same mice shown in panel A. (D) Lineage contribution derived from the My-bi (M) and Ly-bi (L) HSCs in the mixed hosts. Each panel labeled host 5, 6, 7, and 8 corresponds to the mix 5, 6, 7, and 8, respectively, in panel B. Bars labeled L show the cells derived from the Ly-bi HSCs and bars labeled M show the cells derived from the My-bi HSCs in each host. (E) The percentage of myeloid and lymphoid cells derived from the 2 HSC clones shown in panel D was combined for each host.

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