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.