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Sustained blood cell production depends on divisions by hematopoietic stem cells (HSCs)
that yield both differentiating progeny as well as new HSCs via self-renewal. Differentiating
progeny remain capable of self-renewal, but only HSCs sustain self-renewal through
successive divisions securely enough to maintain clones that persist life-long. Until
recently, the first identified next stage consisted of "short-term" reconstituting
cells able to sustain clones of differentiating cells for only 4-6 weeks. Here we
expand evidence for a numerically dominant "intermediate-term" multipotent HSC stage
in mice whose clones persist for 6-8 months before becoming extinct and that are separable
from both short-term as well as permanently reconstituting "long-term" HSCs. The findings
suggest that the first step in stem cell differentiation consists not in loss of initial
capacity for serial self-renewal divisions, but rather in loss of mechanisms that
stabilize self-renewing behavior throughout successive future stem cell divisions.
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