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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2400-2408.
Prepublished online as a Blood First Edition Paper on November 16, 2007; DOI 10.1182/blood-2007-07-102087.
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Submitted July 19, 2007
Accepted October 30, 2007
Globin switches in yolk-sac-like primitive and fetal-like definitive red blood cells produced from human embryonic stem cells
Caihong Qiu, Emmanuel N Olivier, Michelle Velho, and Eric E Bouhassira*
Einstein Center for Human Embroyonic Stem Cell Research, Department of Medicine, Hematology, and Department of Cell Biology, Albert Einstein College Of Medicine, Bronx, NY, United States
* Corresponding author; email: bouhassi{at}aecom.yu.edu.
We have previously shown that co-culture of hESCs for 14 days with immortalized fetal hepatocytes yields CD34+ cells that can be expanded in serum-free liquid culture into large numbers of megaloblastic nucleated erythroblasts resembling yolk-sac derived cells. We show here that these primitive erythroblasts undergo a switch in hemoglobin composition during late terminal erythroid maturation with the basophilic erythroblasts expressing predominantly Hb Gower I ( 2 2) and the orthochromatic erythroblasts hemoglobin Gower II ( 22). This suggests that the switch from Hb Gower I to Hb Gower II, the first hemoglobin switch in humans is a maturation switch not a lineage switch. We also show that extending the co-culture of the hESCs with immortalized fetal hepatocytes to 35 days yields CD34+ cells that differentiate into more developmentally mature, fetal liver-like erythroblasts, that are smaller, express mostly fetal hemoglobin, and can enucleate. We conclude that hESC-derived erythropoiesis closely mimics early human development since the first 2 human hemoglobin switches are recapitulated, and since yolk-sac-like and fetal liver-like cells are sequentially produced. Development of a method that yields erythroid cells with an adult phenotype remains necessary, since the most mature cells that can be produced with current systems express less than 2% adult  -globin.
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