Embryonic → fetal Hb switch in humans: Studies on erythroid bursts generated by embryonic progenitors from yolk sac and liver

The synthesis of embryonic (ζ, ε), fetal (α, γ), and adult (β) globin was evaluated in human yolk sacs (YS) and livers at different ontogenic stages (i.e., from 6 through 10-12 wk of age) by means of analytical isoelectric focusing. Globin production was comparatively evaluated in vivo (i.e., in directly labeled erythroblasts from YS and liver) and in vitro [i.e., in erythroid bursts generated in culture by erythroid burst-forming units (BFU-E) from the same erythropoietic tissues]. Erythroid bursts generated in vitro by BFU-E from 6-wk livers and YS show essentially a 'fetal' globin synthetic pattern: this is in sharp contrast to the 'embryonic' pattern in corresponding liver and YS erythroblasts directly labeled in vivo. The in vitro phenomenon suggests that (i) 6-wk BFU-E constitute a new generation of progenitors, which have already switched from an embryonic to a fetal program, and/or (ii) expression of their fetal program is induced by unknown in vitro factor(s), which may underlie the in vivo switch at later ontogenic stages. It is emphasized that 6- to 7-wk BFU-E are endowed with the potential for in vitro synthesis of not only ε and γ-chains but also some β-globin. In general, we observed an inverse correlation between the levels of ε- and β-chain synthesis. These results, together with previous studies on fetal, perinatal, and adult BFU-E, are compatible with models suggesting that in ontogeny the chromatin configuration is gradually modified at the level of the non-α gene cluster, thus leading to a 5' → 3' activation of globin genes in a balanced fashion.