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Embryonic----Fetal Hb switch in humans: studies on erythroid bursts generated by embryonic progenitors from yolk sac
Insights
Human embryonic and fetal globin synthesis in yolk sacs and livers was studied. In vitro culture of progenitors revealed a fetal globin pattern, suggesting a switch in developmental programs.
Area of Science:
- Developmental Biology
- Hematopoiesis
- Molecular Genetics
Background:
- Human globin synthesis shifts from embryonic to fetal and adult forms during development.
- Yolk sac and liver are key sites of early erythropoiesis.
Purpose of the Study:
- To investigate embryonic, fetal, and adult globin synthesis in human yolk sacs and livers during early ontogeny.
- To compare globin production in vivo versus in vitro using progenitor cells.
Main Methods:
- Analytical isoelectric focusing was used to evaluate globin synthesis.
- Direct labeling of erythroblasts in vivo and erythroid burst-forming unit (BFU-E) cultures in vitro were employed.
Main Results:
- In vitro cultures of 6-week BFU-E from yolk sac and liver showed a fetal globin pattern, contrasting with the embryonic pattern observed in vivo.
- BFU-E from 6-7 weeks demonstrated potential for synthesizing epsilon, gamma, and some beta-globin chains.
- An inverse correlation between epsilon- and beta-chain synthesis levels was observed.
Conclusions:
- Early BFU-E may represent a progenitor generation that has already transitioned to a fetal program or are induced by in vitro factors.
- These findings support models of gradual chromatin modification and sequential globin gene activation during human ontogeny.
Abstract:
The synthesis of embryonic (zeta, epsilon), fetal (alpha, gamma), and adult (beta) 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 invitro 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 epsilon- and gamma-chains but also some beta-globin. In general, we observed an inverse correlation between the levels of epsilon- and beta-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-alpha gene cluster, thus leading to a 5'----3' activation of globin genes in a balanced fashion.