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An addendum to this article has been published: Eshghi et al., J. Cell Biol. 181 (2) 395
Published online
doi:10.1083/jcb.200702080
The Journal of Cell Biology, Vol. 177, No. 5, 871-880
The Rockefeller University Press, 0021-9525 $30.00
© Eshghi et al.
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Article

{alpha}4ß1 integrin and erythropoietin mediate temporally distinct steps in erythropoiesis: integrins in red cell development



Shawdee Eshghi1,2,6, Mariette G. Vogelezang3, Richard O. Hynes3,4, Linda G. Griffith1,2,5, and Harvey F. Lodish1,2,4,6

1 Division of Biological Engineering, 2 Biotechnology Process Engineering Center, 3 Center for Cancer Research, 4 Department of Biology, and 5 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139
6 Whitehead Institute for Biomedical Research, Cambridge, MA 02142

Correspondence to Harvey F. Lodish: lodish{at}wi.mit.edu

Erythropoietin (Epo) is essential for the terminal proliferation and differentiation of erythroid progenitor cells. Fibronectin is an important part of the erythroid niche, but its precise role in erythropoiesis is unknown. By culturing fetal liver erythroid progenitors, we show that fibronectin and Epo regulate erythroid proliferation in temporally distinct steps: an early Epo-dependent phase is followed by a fibronectin-dependent phase. In each phase, Epo and fibronectin promote expansion by preventing apoptosis partly through bcl-xL. We show that {alpha}4, {alpha}5, and ß1 are the principal integrins expressed on erythroid progenitors; their down-regulation during erythropoiesis parallels the loss of cell adhesion to fibronectin. Culturing erythroid progenitors on recombinant fibronectin fragments revealed that only substrates that engage {alpha}4ß1-integrin support normal proliferation. Collectively, these data suggest a two-phase model for growth factor and extracellular matrix regulation of erythropoiesis, with an early Epo-dependent, integrin-independent phase followed by an Epo-independent, {alpha}4ß1-integrin–dependent phase.

Abbreviations used in this paper: BFU-E, burst-forming unit–erythroid; CFU-E, colony-forming unit–erythroid; Epo, erythropoietin; FAK, focal adhesion kinase.


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