Erythropoietin Signaling Inhibits the Short-Term Marrow Reconstitution.

Murine hematopoietic stem cells (HSCs) transfected with gain-of-function human erythropoietin receptor (EPOR ) transgene were reported to have a competitive advantage over wild type mouse HSCs in a bone marrow transplantation (BMT) model (Kirby, Blood; 95(12):3710, 2000). However, EpoRs may not be normally expressed in early progenitor/stem cells, moreover, whether the Epo/EpoR signaling plays a role on homing and repopulating of hematopoietic progenitor/stem cells is also unknown. Our lab has previously created a mouse model harboring either a knocked-in human wild type ( wthEPOR ) hypomorphic gene or a mutant human gain-of-function EPOR ( mthEPOR ) gene into the mouse EPOR locus (Divoky, PNAS; 98(3):986, 2001). The wthEPOR mice are anemic, while mthEpoR mice are polycythemic. We tested the possible advantage of mthEPOR HSCs in the competitive bone marrow (BM) transplantation assay using C57/Bl6 congenic mice. BM from wthEPOR (CD45.1/45.2 heterozygous or CD45.1) and mthEPOR (CD45.2) mice were co-transplanted (1:1 ratio) into lethally irradiated (137Cs >11Gy split) normal recipients (CD45.1 or CD45.1/45.2). Unexpectedly, in three independent groups the peripheral blood chimerism derived from wthEPOR-bearing cells significantly out-competed the mthEPOR-bearing cells two weeks after BMT (52% vs. 40%, 52% vs. 45% and 50% vs. 42%, n=11, 8 and 6, p<0.01). Furthermore, administration of exogenous Epo (10U/day/mouse) further impaired peripheral blood engraftment (including Ter119+ erythroid lineages) of mthEPOR cells (45% vs. 39%, n=8, p<0.05) though the relative proportion of erythroid cells within the engraftment was increased. Thus, an enhanced Epo/EpoR signaling interferes with the short-term repopulation of hematopoietic progenitors resulting in a decreased engraftment, possibly by interfering with homing. A possible long-term advantage of mthEPOR HSCs is being evaluated in ongoing studies; however, these short term data suggest that Epo administration to BM transplant patients may impede engraftment. ![Figure][1] Figure [1]: pending:yes