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/G2/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/G2/M was reversed when cells were allowed to progress into G1 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/G2/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.
Michelle B. Bowie, Kristen D. McKnight, David G. Kent, Lindsay McCaffrey, Pamela A. Hoodless, Connie J. Eaves
The cycling activity of CRUs is downregulated between 3 and 4 weeks of age.
Shown are the number of CRUs per 105 initial total viable cells. FL cells were depleted of Ter119+ cells; for the 3- and 4-wk BM cells, all lin+ cells except Mac1+ cells were removed; and for the 10-wk BM cells, all lin+ cells including Mac1+ cells were removed. Values are mean ± SEM from data pooled from at least 3 experiments per tissue. **