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Blood, 15 July 2007, Vol. 110, No. 2, pp. 509-518.
Prepublished online as a Blood First Edition Paper on April 2, 2007; DOI 10.1182/blood-2006-11-056465.
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Submitted November 7, 2006
Accepted March 28, 2007
Erythropoietin modulation of podocalyxin, and a proposed erythroblast niche
Pradeep Sathyanarayana, Madhu P Menon, Olga Bogacheva, Oleg Bogachev, Knut Niss, William S Kapelle, Estelle Houde, Jing Fang, and Don M Wojchowski*
Stem & Progenitor Cell Biology Program, Maine Medical Center Research Institute, Scarborough, ME
Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME
Global Research and Development, Pfizer Inc., Groton, CT
* Corresponding author; email: wojchd{at}mmc.org.
Epo's erythropoietic capacity is ascribed largely to its anti-apoptotic actions. In part via gene profiling of bone marrow erythroblasts, Epo is now shown to selectively down-modulate the adhesion/migration factors chemokine receptor-4 (Cxcr4) and integrin alpha-4 (Itga4), and to up-modulate growth differentiation factor-3 (Gdf3), oncostatin-M (Onco-M) and podocalyxin like-1 (PODXL). For PODXL, Epo dose- dependent expression of this CD34-related sialomucin was discovered in KitposCD71high pro-erythroblasts, and was sustained at subsequent KitnegCD71high and Ter119pos stages. In vivo, Epo markedly induced PODXL expression in these progenitors and in marrow-resident reticulocytes. This further was associated with a rapid release of PODXLpos reticulocytes to blood. As studied in erythroblasts expressing minimal Epo receptor (EpoR) alleles, efficient PODXL induction proved to depend upon an EpoR-PY343 Stat5 binding site. Moreover, in mice expressing an EpoR-HM F343 allele, compromised Epo-induced PODXL expression correlated with abnormal anucleated red cell representation in marrow. By modulating this select set of cell surface adhesion molecules and chemokines, Epo is proposed to mobilize erythroblasts from a hypothesized stromal niche, and possibly promote reticulocyte egress to blood.
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