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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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HEMATOPOIESIS
Erythropoietin modulation of podocalyxin and a proposed erythroblast niche
Pradeep Sathyanarayana1,
Madhu P. Menon1,
Olga Bogacheva1,
Oleg Bogachev1,
Knut Niss2,
William S. Kapelle1,
Estelle Houde1,
Jing Fang1, and
Don M. Wojchowski1
1 Stem and Progenitor Cell Biology Program and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME;
2 Pfizer Global Research and Development, Groton, CT
Epo's erythropoietic capacity is ascribed largely to its antiapoptotic 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 (OncoM), and podocalyxin like-1 (PODXL). For PODXL, Epo dose–dependent expression of this CD34-related sialomucin was discovered in Kit+CD71high proerythroblasts and was sustained at subsequent Kit–CD71high and Ter119+ stages. In vivo, Epo markedly induced PODXL expression in these progenitors and in marrow-resident reticulocytes. This was further associated with a rapid release of PODXL+ reticulocytes to blood. As studied in erythroblasts expressing minimal Epo receptor (EpoR) alleles, efficient PODXL induction proved dependence on 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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