The relative quiescence of hematopoietic stem cells in nonhuman primates

Quiescence has been thought to be required for the retention of the full biological potential of pluripotent hematopoietic stem cells (PHSCs). This hypothesis has been challenged recently by the observation that all murine PHSCs cycle continuously and constantly contribute to steady-state blood cell production. It was asked whether these observations could be extrapolated to describe hematopoiesis in higher mammals. In this series of experiments, the replicative history of PHSCs was examined in baboons by continuously administering bromodeoxyuridine (BrdU) for more than 85 weeks. The results indicate that under steady-state conditions, PHSCs remain largely quiescent but do cycle, albeit at a far lower rate than previously reported for rodent PHSCs. BrdU-labeled cycling PHSCs and progenitor cells were shown to have an extensive proliferative capacity and to contribute to blood cell production for prolonged periods of time. The proportion of PHSCs entering cell cycle could, however, be rapidly increased by the in vivo administration of granulocyte-colony stimulating factor. These data indicate that during steady-state hematopoiesis, baboon PHSCs require prolonged periods of time to cycle and that the proportion of PHSCs in cycle is not fixed but can be altered by external stimuli. The relative quiescence of PHSCs observed in this nonhuman primate model, in contrast to murine PHSCs, might explain the current barriers to genetic modification and ex vivo expansion of human PHSCs.