Cellular regulation of hemoglobin switching: evidence for inverse relationship between fetal hemoglobin synthesis and degree of maturity of human erythroid cells.

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Abstract
To investigate whether the level of maturity of human erythroid cells influences the expression of the fetal Hb program, the relative production of fetal Hb, Hb F and Hb A were studied during maturation of erythroid clones produced in vitro by adult or neonatal erythroid stem cells. In adult and neonatal cell cultures, clones composed of immature erythroblasts showed a significantly higher Hb F/Hb A ratio compared to the mature clones. Culture conditions enhancing erythroid cell maturity (such as an increase in level of erythropoietin or culture time) decreased the relative synthesis of Hb F in maturing erythroid cells. Direct immunofluorescence studies demonstrated earlier production of Hb F compared with Hb A during maturation of adult-origin Hb F-synthesizing clones. The final expression of Hb F was influenced by the degree of maturity of the terminally differentiated cells and, in addition to regulation at the level of erythroid stem cells, there was apparently control of Hb F expression during erythroblast maturation. The inverse relationship between Hb F expression and level of cell maturity suggests that a regulatory mechanism operating throughout the process of erythroid stem cell differentiation/erythroblast maturation decreases the potential of Hb F expression as development of the erythroid cell advances.