Immature erythroblasts with extensive ex vivo self-renewal capacity emerge from the early mammalian fetus.
In the hematopoietic hierarchy, only stem cells are thought to be capable of long-term self-renewal. Erythroid progenitors derived from fetal or adult mammalian hematopoietic tissues are capable of short-term, or restricted (10(2)- to 10(5)-fold), ex vivo expansion in the presence of erythropoietin, stem cell factor, and dexamethasone. Here, we report that primary erythroid precursors derived from early mouse embryos are capable of extensive (10(6)- to 10(60)-fold) ex vivo proliferation. These cells morphologically, immunophenotypically, and functionally resemble proerythroblasts, maintaining both cytokine dependence and the potential, despite prolonged culture, to generate enucleated erythrocytes after 3-4 maturational cell divisions. This capacity for extensive erythroblast self-renewal is temporally associated with the emergence of definitive erythropoiesis in the yolk sac and its transition to the fetal liver. In contrast, hematopoietic stem cell-derived definitive erythropoiesis in the adult is associated almost exclusively with restricted ex vivo self-renewal. Primary primitive erythroid precursors, which lack significant expression of Kit and glucocorticoid receptors, lack ex vivo self-renewal capacity. Extensively self-renewing erythroblasts, despite their near complete maturity within the hematopoietic hierarchy, may ultimately serve as a renewable source of red cells for transfusion therapy.
Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
Samantha J
SJ
England
Kathleen E
KE
McGrath
Jenna M
JM
Frame
James
J
Palis
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004900:Erythroblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005333:Fetus / Q000166:cytology*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008322:Mammals / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015017:Yolk Sac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D017467:Receptors, Erythropoietin; D011965:Receptors, Glucocorticoid; C029360:hydrocortisone receptor; D003907:Dexamethasone; D019009:Proto-Oncogene Proteins c-kit