Research ArticleKidney Disease

Human pluripotent stem cell–derived erythropoietin-producing cells ameliorate renal anemia in mice

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Science Translational Medicine  27 Sep 2017:
Vol. 9, Issue 409, eaaj2300
DOI: 10.1126/scitranslmed.aaj2300

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Cell therapy for renal anemia

Erythropoietin dysregulation is a hallmark of renal anemia. Although recombinant erythropoietin treatment is beneficial and safe, more physiological therapies are required. Hitomi et al. have developed a differentiation protocol for erythropoietin-producing cells from human and mouse iPSCs and ESCs. These cells produced and secreted functional erythropoietin protein in a hypoxia-dependent manner. Transplantation of these cells into a mouse model ameliorated renal anemia. From the perspective of basic research, erythropoietin-producing cells may be a useful tool for investigating the molecular mechanisms of erythropoietin production and secretion. From the perspective of clinical research, these results may provide a physiological therapeutic agent for treating renal anemia.

Abstract

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.

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