Erythropoietin modulation of podocalyxin and a proposed erythroblast niche.
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(+)CD71(high) proerythroblasts and was sustained at subsequent Kit(-)CD71(high) 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.
Sathyanarayana
Pradeep
P
Stem and Progenitor Cell Biology Program and Center for Molecular Medicine, Maine Medical Center Research Institute, Scarborough, ME 04074, USA.
Menon
Madhu P
MP
Bogacheva
Olga
O
Bogachev
Oleg
O
Niss
Knut
K
Kapelle
William S
WS
Houde
Estelle
E
Fang
Jing
J
Wojchowski
Don M
DM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000502:physiology; D004900:Erythroblasts / Q000187:drug effects / Q000502:physiology*; D004921:Erythropoietin / Q000494:pharmacology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D017467:Receptors, Erythropoietin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012795:Sialoglycoproteins / Q000187:drug effects / Q000235:genetics*; D052116:Sialomucins / Q000187:drug effects / Q000235:genetics
D017467:Receptors, Erythropoietin; D012795:Sialoglycoproteins; D052116:Sialomucins; C001643:podocalyxin; D004921:Erythropoietin