title: Globin switches in yolk sac-like primitive and fetal-like definitive red blood cells produced from human embryonic stem cells.
abstract: We have previously shown that coculture of human embryonic stem cells (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 (Hb) composition during late terminal erythroid maturation with the basophilic erythroblasts expressing predominantly Hb Gower I (zeta(2)epsilon(2)) and the orthochromatic erythroblasts hemoglobin Gower II (alpha(2)epsilon(2)). 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 coculture 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 because the first 2 human hemoglobin switches are recapitulated, and because 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, because the most mature cells that can be produced with current systems express less than 2% adult beta-globin mRNA.
authors.affiliation: Einstein Center for Human Embryonic Stem Cell Research, Department of Medicine, Hematology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Caihong
authors.initials: C
authors.lastname: Qiu
authors.forename: Emmanuel N
authors.initials: EN
authors.lastname: Olivier
authors.forename: Michelle
authors.initials: M
authors.lastname: Velho
authors.forename: Eric E
authors.initials: EE
authors.lastname: Bouhassira
mesh_terms: D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D002454:Cell Differentiation; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D004912:Erythrocytes / Q000166:cytology / Q000502:physiology*; D005333:Fetus; D005914:Globins / Q000502:physiology*; D006454:Hemoglobins / Q000502:physiology*; D006455:Hemoglobins, Abnormal / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D015017:Yolk Sac / Q000502:physiology*
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D006454:Hemoglobins; D006455:Hemoglobins, Abnormal; C030446:hemoglobin Gower; D005914:Globins