Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
Sci Transl Med. 2017 Sep 27;9(409). doi: 10.1126/scitranslmed.aaj2300.
The production of erythropoietin (EPO) by the kidneys, a principal hormone for the hematopoietic system, is reduced in patients with chronic kidney disease (CKD), eventually resulting in severe anemia. Although recombinant human EPO treatment improves anemia in patients with CKD, returning to full red blood cell production without fluctuations does not always occur. We established a method to generate EPO-producing cells from human induced pluripotent stem cells (hiPSCs) by modifying previously reported hepatic differentiation protocols. These cells showed increased EPO expression and secretion in response to low oxygen conditions, prolyl hydroxylase domain-containing enzyme inhibitors, and insulin-like growth factor 1. The EPO protein secreted from hiPSC-derived EPO-producing (hiPSC-EPO) cells induced the erythropoietic differentiation of human umbilical cord blood progenitor cells in vitro. Furthermore, transplantation of hiPSC-EPO cells into mice with CKD induced by adenine treatment improved renal anemia. Thus, hiPSC-EPO cells may be a useful tool for clarifying the mechanisms of EPO production and may be useful as a therapeutic strategy for treating renal anemia.
肾脏产生的促红细胞生成素（EPO）是造血系统的主要激素，在慢性肾脏病（CKD）患者中会减少，最终导致严重贫血。虽然重组人 EPO 治疗可改善 CKD 患者的贫血，但并不总能恢复到完全无波动的红细胞生成。我们通过修改先前报道的肝分化方案，从人诱导多能干细胞（hiPSC）中建立了一种产生 EPO 产生细胞的方法。这些细胞在低氧条件、脯氨酰羟化酶结构域包含酶抑制剂和胰岛素样生长因子 1 作用下，EPO 的表达和分泌增加。hiPSC 来源的 EPO 产生细胞（hiPSC-EPO）分泌的 EPO 蛋白在体外诱导人脐带血祖细胞的红细胞生成分化。此外，将 hiPSC-EPO 细胞移植到腺嘌呤处理诱导的 CKD 小鼠中，可改善肾脏贫血。因此，hiPSC-EPO 细胞可能是阐明 EPO 产生机制的有用工具，并且可能作为治疗肾性贫血的治疗策略有用。
