Intermediate-Term Hematopoietic Stem Cells with Extended but Time-Limited Reconstitution Potential

SummarySustained 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.

► Individual purified HSCs show sustained or transient reconstitution ► Intermediate-term hematopoietic stem cells (ITRCs) have prolonged but limited lifespan ► ITRCs outnumber long-term cells in highly purified fractions ► Intermediate-term cells enriched based on integrin α2 expression