HEMATOPOIETIC STEM-CELL DEFICIENCIES IN MICE LACKING C-MPL, THE RECEPTOR FOR THROMBOPOIETIN

Thrombopoietin (TPO) acts as a lineage-specific late-acting factor to stimulate megakaryocyte and platelet formation, However, analysis of m ice lacking either the cytokine or its receptor, c-Mpl, also revealed deficiencies in progenitor cells of multiple hematopoietic lineages, s uggesting that TPO signaling may play an important role in the regulat ion of the hematopoietic stem cell compartment. To investigate this hy pothesis, we determined preprogenitor and colony forming unit-spleen ( CFU-S) numbers and analyzed the long-term hematopoietic repopulating c apacity of bone marrow cells from mpl(-/-) mice.mpl(-/-) mice had 4- t o 12-fold fewer preprogenitor cells than wild type mice, In irradiated normal recipients, mpl(-/-) bone marrow generated 8- to 10-fold fewer spleen colonies than wild-type marrow at both 8 and 12 days after tra nsplantation. This defect was intrinsic to the transplanted hematopoie tic cells, as the microenvironment of mpl(-/-) recipients supported si milar CFU-S growth to that observed in wild-type recipients, In defini tive assays of stem cell function, bone marrow cells from mpl(-/-) mic e failed to compete effectively with normal cells for long-term recons titution of the hematopoietic organs of irradiated recipients, even wh en transplanted in 10-fold excess, Serial transplantation studies furt her suggested that stem cell self-renewal also may be compromised in m pl(-/-) mice, These data imply that TPO, signaling through c-Mpl, play s a vital physiological role in the regulation of hematopoietic stem c ell production and function.