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

Abstract

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.

CD166 regulates human and murine hematopoietic stem cells and the hematopoietic niche

“…15 As shown in Figure 1A, CD166 and CD150 fractionated LSK48 16 or LT-HSC with a limited, but consistent, repopulating potential. Limiting dilution analysis (LDA) ( Figure 1D) revealed that the frequency of LT-HSC was highest among CD166 Figure 1I) (FMO controls shown in supplemental Figure 1B).…”

HIV-1 infection of hematopoietic progenitor cells in vivo in humanized mice

“…19,20 In these studies, all patients were on long-term, suppressive pharmacotherapy. Because of their relatively short lifespan, 39 we do not believe intermediate progenitors represent a stable viral reservoir. However, intermediate progenitors could potentially be a dynamic reservoir maintained by low-level viremia in the absence of HAART and as such may warrant further study as a novel target for antiviral therapy.…”

Asymmetric segregation and self-renewal of hematopoietic stem and progenitor cells with endocytic Ap2a2

“…To circumvent this and to further investigate the Ap2a2-quiescence link, we isolated from independent sorts batches of 30-50 cells of the LT-HSC and multipotent intermediate-term HSC (IT-HSC) 28 populations while in quiescence and in cell cycle for Ap2a2 expression. This IT-HSC population, isolated in the CD49b hi rhodamine low LSK fraction and separable from the classic short-term repopulating HSCs, generates multilineage clones that expand through to 8 weeks.…”