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

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.