Gabbianelli M, Pelosi E, Bassano E, Labbaye C, Petti S, Rocca E, Tritarelli E, Miller B A, Valtieri M, Testa U
Department of Hematology-Oncology, Istituto Superiore di Sanità Rome, Italy.
Blood. 1989 Dec;74(8):2657-67.
Reactivation of fetal hemoglobin (HbF, alpha 2 gamma 2) synthesis was previously reported in normal human adult erythroblast colonies ("bursts") generated by erythroid progenitors (BFU-E) in fetal calf serum-supplemented (FCS+) semisolid cultures stimulated with erythropoietin (Ep). Our studies focused on the reactivation of HbF synthesis in normal adult erythroid bursts generated by peripheral blood mononuclear cells (PBMCs) seeded in FCS+ methylcellulose culture. Reactivation is almost totally suppressed when (a) PBMCs are grown in optimized FCS- culture, or (b) PBMCs are first stringently depleted of monocytes and then plated in FCS+ medium (ie, BFU-E growth in FCS+ Mo- culture). In both experimental conditions, the proliferation of lymphocytes and macrophages interspersed among colonies is drastically reduced, and the cloning efficiency of granulocyte-macrophage (GM) progenitors is sharply diminished. In either case, addition of biosynthetic GM colony-stimulating factor (GM-CSF) induces a dose-related increase of HbF synthesis up to the level in FCS+ culture, with even more elevated values on delayed addition of Ep. A dose-related increase was also observed in erythroblast clones generated by highly purified BFU-E. These results suggest that reactivation of HbF synthesis in normal adults is at least in part mediated by GM-CSF. Furthermore, they imply intriguing hypotheses on the mechanism(s) of perinatal Hb switching. Finally, they raise the possibility of reactivation of HbF synthesis in beta-thalassemia and sickle cell anemia by GM-CSF therapy.
先前有报道称，在促红细胞生成素（Ep）刺激的、添加胎牛血清（FCS+）的半固体培养物中，由红系祖细胞（BFU-E）生成的正常人成年红细胞集落（“爆发”）中，胎儿血红蛋白（HbF，α2γ2）合成重新激活。我们的研究聚焦于在接种于FCS+甲基纤维素培养物中的外周血单个核细胞（PBMC）所生成的正常成年红细胞爆发中HbF合成的重新激活。当（a）PBMC在优化的无FCS培养物中生长，或（b）PBMC首先被严格去除单核细胞，然后接种于FCS+培养基中（即，在FCS+无单核细胞培养物中BFU-E生长）时，重新激活几乎被完全抑制。在这两种实验条件下，集落间散布的淋巴细胞和巨噬细胞的增殖显著减少，粒细胞-巨噬细胞（GM）祖细胞的克隆效率急剧降低。在任何一种情况下，添加生物合成的GM集落刺激因子（GM-CSF）都会诱导HbF合成呈剂量相关增加，直至达到FCS+培养物中的水平，在延迟添加Ep时数值甚至更高。在由高度纯化的BFU-E生成的成红细胞克隆中也观察到剂量相关增加。这些结果表明，正常成年人中HbF合成的重新激活至少部分由GM-CSF介导。此外，它们暗示了关于围产期血红蛋白转换机制的有趣假设。最后，它们提出了通过GM-CSF治疗在β地中海贫血和镰状细胞贫血中重新激活HbF合成的可能性。
