Human hemoglobin switching: insights from studies of erythroid cultures

Clonal erythroid cultures have been used in the investigation of the cellular mechanisms underlying the switch from fetal to adult Hb formation during ontogeny and the expression of fetal hemoglobin in adult life. It has been shown that adult BFUes have the potential to form F cells and A cells in culture. The cellular segregation in the expression of Hb F within a clone leads to the formation of characteristic bursts displaying a bimorphic F+/F-pattern of Hb F expression. Analysis of distribution of F-expressing and not F-expressing subclones and sectors among bursts of various sizes is compatible with the assumption that progenitor cells exercise options on whether they will or they will not form progeny expressing the Hb F phenotype. Distributions of Hb F expressing subclones among bursts fit the expectations of a stochastic model; probabilities for F expression in the adult erythroid cells may be influenced by the environment in which the cells differentiate and mature. Experimental data from cultures of progenitors from earlier stages of human development indicate that the change in globin expression during ontogeny is controlled at the level of progenitor cells. Observations of Hb F levels produced by single erythroid bursts of the neonate make it unlikely that hemoglobin switching during ontogeny is accomplished through replacement of stem cell lines. The findings in erythroid cultures are compatible with the hypothesis that hemoglobin switching during ontogeny is accomplished through intrinsic or interactive changes in the programs of differentiation of progenitors.