Fibach E, Schechter A N, Noguchi C T, Rodgers G P
Department of Haematology, Hadassah University Hospital, Jerusalem, Israel.
Br J Haematol. 1994 Sep;88(1):39-45. doi: 10.1111/j.1365-2141.1994.tb04974.x.
In order to clarify the mechanism of the effect of erythropoietin (Epo) on the fetal haemoglobin (HbF) phenotype of peripheral erythrocytes, we studied the dose-response effect of Epo on HbF production by erythroid precursors derived from the peripheral blood of normal adult individuals and grown in a two-phase liquid culture system. The proportion of HbF out of the total haemoglobin (Hb) content (%HbF) was dependent on the duration of exposure to Epo; on day 6 it comprised up to 15%, but dropped to < 2% on day 14. Both cell yield and cellular Hb content were markedly increased by high (1 U/ml) Epo, compared to normal physiological (20-50 mU/ml) levels, but neither the initial nor final %HbF were dependent on the increased Epo dose. However, when cells grown with high Epo were transferred on day 7 to low Epo, their progeny contained by day 14 a higher %HbF as compared to cells that were continuously exposed to high Epo. This was accompanied by acceleration and synchronization of their maturation process, as evidenced by their morphology, density and size, and restriction on cell multiplication, as indicated by the lower cell yield. These results are consistent with the following model. As early erythroid precursors, with relatively high HbF, mature under steady-state levels of Epo, HbA production predominates and HbF is diluted. However, when such precursors are switched from high to low levels of Epo they undergo a synchronized, accelerated maturation which shortens the period of HbA production, leading to a decreased Hb content and a relatively high proportion of HbF. This mechanism may contribute to the elevated HbF observed following Epo administration (due to short half-life of Epo in vivo), and might also explain the HbF-augmenting effect of Epo administered together with hydroxyurea observed in patients with sickle cell anaemia.
为了阐明促红细胞生成素（Epo）对外周红细胞胎儿血红蛋白（HbF）表型的作用机制，我们研究了Epo对源自正常成年人外周血并在两相液体培养系统中生长的红系前体细胞产生HbF的剂量反应效应。HbF占总血红蛋白（Hb）含量的比例（%HbF）取决于暴露于Epo的持续时间；在第6天，其占比高达15%，但在第14天降至<2%。与正常生理水平（20 - 50 mU/ml）相比，高剂量（1 U/ml）的Epo显著提高了细胞产量和细胞内Hb含量，但初始和最终的%HbF均不依赖于增加的Epo剂量。然而，当在第7天将用高剂量Epo培养的细胞转移至低剂量Epo环境中时，与持续暴露于高剂量Epo的细胞相比，其后代在第14天时含有更高比例的HbF。这伴随着它们成熟过程的加速和同步化，从其形态、密度和大小可得到证明，同时细胞增殖受到限制，表现为细胞产量降低。这些结果与以下模型一致。作为早期红系前体细胞，具有相对较高的HbF，在Epo的稳态水平下成熟，HbA的产生占主导，HbF被稀释。然而，当这些前体细胞从高剂量Epo转换为低剂量Epo时，它们会经历同步、加速的成熟过程，这缩短了HbA的产生期导致Hb含量降低以及HbF比例相对升高。这种机制可能有助于解释Epo给药后（由于Epo在体内半衰期短）观察到的HbF升高现象，也可能解释了在镰状细胞贫血患者中观察到的Epo与羟基脲联合给药时HbF增加的效应。
