Erythropoietin receptor signaling regulates both erythropoiesis and megakaryopoiesis in vivo.
Transgenic expression of a gain-of-function truncated mouse erythropoietin receptor gene (EpoR) leads to expansion of the HSC pool in response to human erythropoietin (Epo). We have re-examined this observation using a knock-in mouse model, wherein the mouse EpoR gene was replaced in its proper genetic locus by a single copy of either a wild-type human or a polycythemia-inducing truncated human EPOR gene. Bone marrow cells obtained from knock-in mice were transplanted together with competitor bone marrow cells in a model that allows tracking of erythroid, platelet, and leukocyte contributions by each genotype. Secondary transplants were also performed. Stem/progenitor cells were identified phenotypically and isolated for colony-forming assays to evaluate cytokine responsiveness by cells with the wild-type human or truncated human EPOR gene. Augmented Epo signaling increased erythroid repopulation post-transplant as expected, but had no effect on short-term or long-term leukocyte repopulation. However, the wild-type human EPOR knock-in mouse showed decreases in both erythroid and platelet repopulation compared to marrow cells from the mutant human EPOR knock-in mouse or normal B6 animals. These results provide evidence supporting a role for Epo signaling in megakaryopoiesis in vivo and suggest a role for Epo signaling early in hematopoietic development.
Huang
Xiaosong
X
Department of Pathology, University of Utah, Salt Lake City, UT 84132-2408, USA.
Pierce
L Jeanne
LJ
Chen
George L
GL
Chang
Ko-Tung
KT
Spangrude
Gerald J
GJ
Prchal
Josef T
JT
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000187:drug effects; D055879:Gene Knock-In Techniques; D005838:Genotype; D006085:Graft Survival / Q000235:genetics; D006801:Humans; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D020033:Protein Isoforms / Q000032:analysis / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics*; D034061:Thrombopoiesis; D013997:Time Factors; D055544:beta-Globins / Q000032:analysis / Q000235:genetics
D016207:Cytokines; D020033:Protein Isoforms; D017467:Receptors, Erythropoietin; D055544:beta-Globins