Bacon E R, Dalyot N, Filon D, Schreiber L, Rachmilewitz E A, Oppenheim A
Department of Hematology, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Mol Med. 1995 Mar;1(3):297-305.
Understanding the mechanism of developmental regulation of hemoglobin switching has scientific as well as clinical relevance because of the influence of fetal hemoglobin (HbF) production in adulthood on the clinical manifestation of thalassemia and sickle cell anemia. We have previously found that the normal developmental patterns of globin gene expression are recapitulated in an experimental system of primary cultures that support differentiation of erythroid progenitors. We further found that high activities of the transcriptional activators, GATA-1 and SP1, are associated with normal adult erythroid differentiation.
In the present work, we have studied, the activities of GATA-1 and SP1 during differentiation of cultured erythroid progenitors derived from cord blood and from fetal livers, as well as from beta zero-thalassemia patients.
The results showed high GATA-1 binding activity and very low SP1 activity in the fetal liver cultures. This pattern was in contrast to cultures derived from normal adult peripheral blood, in which both GATA-1 and SP1 activities were high. Cord blood cultures showed an additive combination of "adult" and "fetal" patterns. The progenitors derived from a beta zero-thalassemia patient with high HbF production showed "fetal" pattern. On the other hand, in cultures of 2 beta zero-thalassemia patients without high HbF, "adult" pattern was observed.
In the present work, we show that human fetal and adult erythroid progenitors are distinct in their transcription factors, and that the commitment to fetal or adult program occurs at a very early differentiation stage. Our studies also demonstrate that under anemic stress, recruitment of fetal progenitors may occur in adulthood.
由于成年期胎儿血红蛋白（HbF）的产生对地中海贫血和镰状细胞贫血临床表现的影响，了解血红蛋白转换的发育调控机制具有科学及临床意义。我们之前发现，在支持红系祖细胞分化的原代培养实验系统中，珠蛋白基因表达的正常发育模式得以重现。我们还进一步发现，转录激活因子GATA-1和SP1的高活性与正常的成人红系分化相关。
在本研究中，我们研究了源自脐带血、胎儿肝脏以及β0地中海贫血患者的培养红系祖细胞分化过程中GATA-1和SP1的活性。
结果显示，胎儿肝脏培养物中GATA-1结合活性高，而SP1活性极低。这种模式与源自正常成人外周血的培养物相反，后者中GATA-1和SP1活性均较高。脐带血培养物呈现出“成人”和“胎儿”模式的叠加组合。来自一名HbF产量高的β0地中海贫血患者的祖细胞呈现“胎儿”模式。另一方面，在两名无高HbF的β0地中海贫血患者的培养物中观察到“成人”模式。
在本研究中，我们表明人类胎儿和成人红系祖细胞在转录因子方面存在差异，并且向胎儿或成人程序的定向在非常早期的分化阶段就已发生。我们的研究还表明，在贫血应激下，成年期可能会招募胎儿祖细胞。
