Studies of c-Mpl function distinguish the replication of hematopoietic stem cells from the expansion of differentiating clones

Three properties define hematopoietic stem cells (HSCs): their capacity for quiescence and long survival, their ability to self-renew, and their ability to give rise to a multilineage clone of differentiating and maturing blood cells. Although it is likely that different signals regulate these events, this has been difficult to dissect on a molecular level, since HSC division, their fate decisions, and the earliest differentiation events cannot be directly visualized. Our studies of c-Mpl, the cellular receptor for the cytokine thrombopoletin, suggest that c-Mpl does not control HSC numbers, as had been previously argued, but rather facilitates the early expansion of differentiating clones. These experiments provide a strategy to distinguish the actions of HSCs from earliest progenitor cells in vivo and demonstrate that a selective growth advantage at a level distal to HSC can result in a profound effect on multilineage hematopoiesis.