Tsugata Takako, Nikoh Naruo, Kin Tatsuya, Miyagi-Shiohira Chika, Nakashima Yoshiki, Saitoh Issei, Noguchi Yasufumi, Ueki Hideo, Watanabe Masami, Kobayashi Naoya, Shapiro Andrew M James, Noguchi Hirofumi
Natural and Environmental Sciences Program, The Open University of Japan, Chiba, Japan.
Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
Cell Med. 2018 May 29;10:2155179017733177. doi: 10.1177/2155179017733177. eCollection 2018.
The low efficiency of in vitro differentiation of human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (iPSCs) into insulin-producing cells is a crucial hurdle for the clinical implementation of human pluripotent stem cells (PSCs). Our previous investigation into the key factors for the differentiation of PSCs into insulin-producing cells suggested that the expression of GATA binding protein 6 (GATA6) and Gremlin 1 (GREM1) and inhibition of early growth response protein 1 (Egr1) may be important factors. In this study, we investigated the role of Egr1 in pancreas development. The transfection of small interfering RNA (siRNA) of Egr1 in the early phase induced the differentiation of iPSCs derived from fibroblasts (FiPSCs) into pancreatic endoderm and insulin-producing cells. In contrast, the downregulation of Egr1 in the late phase suppressed the differentiation of FiPSCs into pancreatic endoderm and insulin-producing cells. In addition, the overexpression of Egr1 suppressed the differentiation of iPSCs derived from pancreatic cells into pancreatic endoderm and insulin-producing cells. These data suggest that the downregulation of Egr1 in the early phase can efficiently induce the differentiation of iPSCs into insulin-producing cells.
人类胚胎干细胞（hESCs）或人类诱导多能干细胞（iPSCs）体外分化为胰岛素生成细胞的低效率是人类多能干细胞（PSCs）临床应用的关键障碍。我们之前对PSCs分化为胰岛素生成细胞的关键因素进行的研究表明，GATA结合蛋白6（GATA6）和Gremlin 1（GREM1）的表达以及早期生长反应蛋白1（Egr1）的抑制可能是重要因素。在本研究中，我们研究了Egr1在胰腺发育中的作用。在早期转染Egr1的小干扰RNA（siRNA）可诱导成纤维细胞来源的iPSCs（FiPSCs）分化为胰腺内胚层和胰岛素生成细胞。相反，在晚期下调Egr1会抑制FiPSCs分化为胰腺内胚层和胰岛素生成细胞。此外，Egr1的过表达会抑制胰腺细胞来源的iPSCs分化为胰腺内胚层和胰岛素生成细胞。这些数据表明，早期下调Egr1可有效诱导iPSCs分化为胰岛素生成细胞。
