Erythropoietin Modulation of Podocalyxin within an Erythroblast Niche.

Epo’s capacity to promote red cell production is ascribed largely to anti-apoptotic effects on erythroid progenitor pools. Via gene profiling of bone marrow- derived erythroblasts, Epo is now revealed to down-modulate chemokine receptor-4 (Cxcr4) and integrin alpha-4 (Itga4), and to selectively up-modulate the expression of growth differentiation factor 3 (Gdf3), oncostatin-M (Onco-M), and the sialomucin podocalyxin like-1 (PODXL). Epo dose-dependent induction of PODXL was approximately 20 fold; was discovered in Kit^posCD71^high erythroblasts; and peaked at subsequent Kit^negCD71^high and Ter119^pos stages. As studied using minimal knocked-in Epo receptor (EpoR) alleles, efficient PODXL expression depended upon a proximal EpoR PY343 Stat5 binding site. In mice expressing a phosphotyrosine-null EpoR-HM allele, compromised PODXL expression further correlated with an abnormal representation of anucleated red cells in marrow (and with defective Epo-induced production of PODXL^pos reticulocytes). By selectively modulating Gdf3, Onco-M, Cxcr4, Itga-4 and PODXL expression, Epo is proposed to modify a unique erythroid niche, mobilize early-stage erythroblasts, and promote reticulocyte emigration to blood.