Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai (ISMMS), New York, New York, USA.
Department of Biomedical and Neuromotorial Sciences, Alma Mater University, Bologna, Italy.
Stem Cells. 2018 Feb;36(2):172-179. doi: 10.1002/stem.2735. Epub 2017 Dec 5.
In vitro surrogate models of human erythropoiesis made many contributions to our understanding of the extrinsic and intrinsic regulation of this process in vivo and how they are altered in erythroid disorders. In the past, variability among the levels of hemoglobin F produced by adult erythroblasts generated in vitro by different laboratories identified stage of maturation, fetal bovine serum, and accessory cells as "confounding factors," that is, parameters intrinsically wired in the experimental approach that bias the results observed. The discovery of these factors facilitated the identification of drugs that accelerate terminal maturation or activate specific signaling pathways for the treatment of hemoglobinopathies. It also inspired studies to understand how erythropoiesis is regulated by macrophages present in the erythroid islands. Recent cell culture advances have greatly increased the number of human erythroid cells that can be generated in vitro and are used as experimental models to study diseases, such as Diamond Blackfan Anemia, which were previously poorly amenable to investigation. However, in addition to the confounding factors already identified, improvement in the culture models has introduced novel confounding factors, such as possible interactions between signaling from cKIT, the receptor for stem cell factor, and from the glucocorticoid receptor, the cell proliferation potential and the clinical state of the patients. This review will illustrate these new confounding factors and discuss their clinical translation potential to improve our understanding of Diamond Blackfan Anemia and other erythroid disorders. Stem Cells 2018;36:172-179.
体外人类红细胞生成的替代模型为我们理解体内这一过程的外在和内在调节以及它们在红细胞疾病中的变化做出了许多贡献。过去，不同实验室产生的体外成红细胞产生的血红蛋白 F 水平的可变性确定了成熟阶段、胎牛血清和辅助细胞是“混杂因素”，也就是说，这些参数是实验方法固有的，会影响观察到的结果。这些因素的发现促进了鉴定药物的研究，这些药物可以加速终末成熟或激活血红蛋白病治疗的特定信号通路。它还激发了研究，以了解巨噬细胞如何调节红细胞岛上的红细胞生成。最近的细胞培养进展极大地增加了可以在体外产生的人类红细胞数量，并被用作实验模型来研究疾病，例如 Diamond Blackfan 贫血，以前这种疾病很难进行研究。然而，除了已经确定的混杂因素外，培养模型的改进引入了新的混杂因素，例如干细胞因子受体 cKIT 的信号与糖皮质激素受体的信号之间可能存在相互作用、细胞增殖潜力和患者的临床状况。这篇综述将说明这些新的混杂因素，并讨论它们的临床转化潜力，以增进我们对 Diamond Blackfan 贫血和其他红细胞疾病的理解。干细胞 2018；36:172-179。
