Reactivation of fetal hemoglobin in adult stem cell erythropoiesis by transforming growth factor-beta.
Treatment of adult blood-derived stem cells with transforming growth factor (TGF-beta) during the first 3-4 days in culture increases the proportions and absolute numbers of erythroid cells subsequently expressing fetal hemoglobin (F+ cells). The change in F+ cell proportions may be due to globin switching or to selective effects on the expansion of stem cell subpopulations with different globin expression programs. To distinguish between the two mechanisms, we compared the effects of TGF-beta on proliferation and globin expression with the effects of well-researched agents known to increase fetal hemoglobin (HbF) in sickle cell patients. Hydroxyurea suppressed F+ and F- erythroid cells equally and thus did not affect the F+ proportions. Aza-cytidine and sodium butyrate, known reactivators of gamma-globin expression, suppressed F+ and F- cells differentially and increased F+ cell proportions with a dependence on treatment timing similar to that of TGF-beta. In contrast to TGF-beta, these agents had no superimposed stimulatory effect. The data suggest that TGF-beta reactivates gamma-globin expression, combined with a sequential stimulation and suppression of erythropoiesis. The similarities between the actions of TGF-beta and therapeutic reactivators of fetal hemoglobin make it conceivable that TGF-beta may have the potential to increase HbF in patients with beta-hemoglobin disorders.
GeneType Pty, Ltd., Melbourne, Victoria 3065, Australia. ralph@genetype.com.au
Ralph M
RM
Böhmer
D000328:Adult; D018952:Antigens, CD34 / Q000032:analysis; D001374:Azacitidine / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004920:Erythropoiesis / Q000187:drug effects*; D005319:Fetal Hemoglobin / Q000032:analysis / Q000378:metabolism*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D018952:Antigens, CD34; D002087:Butyrates; D006454:Hemoglobins; D016212:Transforming Growth Factor beta; D005319:Fetal Hemoglobin; D001374:Azacitidine; D006918:Hydroxyurea