Growing and aging of hematopoietic stem cells

Figure 1 Growth curves in mouse. A: Hematopoietic stem cell (HSC) growth in mouse, calculated with data from Udroiu et al[54] and Dingli and Pacheco[13]; B: Rates of HSC replication in mouse, calculated from a; C: Rates of HSC replication in humans, data from Sidorov et al[16]; D: Rates of telomere shortening in humans, data from Sidorov et al[16]. HSC: Hematopoietic stem cells.

Figure 2 Numbers of hematopoietic stem cells and total reticulocytes in aging mice. Calculated with data from Morrison et al[32], Magnani et al[55], and Guo et al[56]. HSC: Hematopoietic stem cells.

Figure 3 Model of increased proliferation in aging hematopoietic stem cells. Aged hematopoietic stem cells (HSC) have a reduced productive potential and generate a fraction of ineffective (gray) progenitor cells, thus producing a reduced number of blood cells. This reduced production of blood cells triggers a stimulus to generate more blood cells, which increases the proliferation rate of the hematopoietic compartment. Increased proliferation is accompanied by telomere shortening, which, in turn, makes HSC even more aged. In this way, the absolute number of HSC increases, but the fraction of ineffective HSC also increases. HSC: Hematopoietic stem cells; PC: Progenitor cells; BC: Blood cells.

Figure 4 Epigenetic modifications in hematopoietic stem cells and their progeny. In young hematopoietic stem cells (HSC), self-renewal (S) genes with unmethylated CpG islands (CGI) and activating H3K4me3 are transcribed, while myeloid (M) and lymphoid (L) genes, with both activating H3K4me3 and repressive H3K27me3, are not, being “in pause”. In the progeny of the myeloid lineage, S and L genes are repressed by H3K27me3 and methylated CGI, while M genes are transcribed. Vice versa, in the lymphoid progeny, S and M genes are repressed and L genes are transcribed. In aged HSC, self-renewal genes have more unmethylated CGI, so their transcription is enhanced; moreover, whereas M genes are “in pause”, L ones are already repressed, so the progeny will transcribe myeloid genes but not the lymphoid ones. The analogy with the “play/pause/stop” symbols is taken from Kosan and Godmann[48]. HSC: Hematopoietic stem cells; S: Self-renewal; L: Lymphoid; M: Myeloid; CGI: CpG islands.