Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect

Abstract

The regulation of HSC proliferation and engraftment of the BM is an important but poorly understood process, particularly during ontogeny. Here we show that in mice, all HSCs are cycling until 3 weeks after birth. Then, within 1 week, most became quiescent. Prior to 4 weeks of age, the proliferating HSCs with long-term multilineage repopulating activity displayed an engraftment defect when transiting S/G 2 /M. During these cell cycle phases, their expression of CXC chemokine ligand 12 (CXCL12; also referred to as stromal cell-derived factor 1 [SDF-1]) transiently increased. The defective engrafting activity of HSCs in S/G 2 /M was reversed when cells were allowed to progress into G 1 prior to injection or when the hosts (but not the cells) were pretreated with a CXCL12 antagonist. Interestingly, the enhancing effect of CXCL12 antagonist pretreatment was exclusive to transplants of long-term multilineage repopulating HSCs in S/G 2 /M. These results demonstrate what we believe to be a new HSC regulatory checkpoint during development. They also suggest an ability of HSCs to express CXCL12 in a fashion that changes with cell cycle progression and is associated with a defective engraftment that can be overcome by in vivo administration of a CXCL12 antagonist.

Cell cycle regulation in hematopoietic stem cells

“…Moreover, the quiescent state of HSCs in the adult BM is reached only after a period of active cell cycling and proliferation to generate the blood system during fetal life (Bowie et al, 2006). Hematopoiesis in the embryo is considered to occur in successive waves, with the initial "primitive" wave geared toward the rapid production of red blood cells for oxygen transport but with little HSC activity; the second, or "definitive" wave, is characterized by the generation of all lineages of blood cells and the production of the first engrafting HSCs.…”

“…Although HSC residence in the BM during adulthood is often associated with quiescence, HSCs do not appear to become quiescent immediately upon seeding the BM, as all HSC activity remains confined to the fraction of actively cycling lineage-negative (Lin  ) BM cells in 3-wk-old weanling mice (Bowie et al, 2006). Remarkably, the BM HSC population rapidly switches to a quiescent state by 4 wk of age, with only 5% of total HSCs actively in the cell cycle (defined as S, G 2 , or M phases) thereafter through adult life (Cheshier et al, 1999;Bowie et al, 2006;Kiel et al, 2007) (Fig.…”

“…Remarkably, the BM HSC population rapidly switches to a quiescent state by 4 wk of age, with only 5% of total HSCs actively in the cell cycle (defined as S, G 2 , or M phases) thereafter through adult life (Cheshier et al, 1999;Bowie et al, 2006;Kiel et al, 2007) (Fig. 1).…”

Over-expression of CXCR4 on mesenchymal stem cells augments myoangiogenesis in the infarcted myocardium

“…However, mobilized cells into infarcted tissue are subject to cell death due to insufficient oxygen [2]. SDF-1α and its unique receptor, CXCR4 play an important role in stem cell homing, chemotaxis, expression of adhesion molecules, engraftment [3], proliferation, and survival [4]. CXCR4 expression is endogenously regulated by tissue environmental factors such as cytokines, chemokines, stromal cells, adhesion molecules, myocardial ischemia and proteolytic enzymes [5].…”

Mutation of C/EBPα predisposes to the development of myeloid leukemia in a retroviral insertional mutagenesis screen

“…Hence, we speculate that the HSC population may serve as target for retroviral infection, consistent with the finding that these cells are still in cell cycle at the time of infection, and that disturbance of the HSC population may be responsible for the reduced latency of lymphoid tumors in Cebpa BRM/BRM2 mice. 54 Alternatively, it could be argued that the reduced latency of lymphoid tumors in Cebpa BRM/BRM2 mice could be due to an increase in proliferation of The 168 RISs (out of 182) for which we have obtained accession numbers were subjected to pathway analysis using the Ingenuity and NIH-DAVID software packages. These software packages returned Ingenuity pathways and KEGG pathways, respectively.…”