Tissue-Specific Stem Cells Obtained by Reprogramming of Non-Obese Diabetic (NOD) Mouse-Derived Pancreatic Cells Confer Insulin Production in Response to Glucose.
Tissue-Specific Stem Cells Obtained by Reprogramming of Non-Obese Diabetic (NOD) Mouse-Derived Pancreatic Cells Confer Insulin Production in Response to Glucose.
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DOI：
10.1371/journal.pone.0163580
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Noguchi H
中科院分区：
文献类型：
--
作者：
Saitoh I;Sato M;Soda M;Inada E;Iwase Y;Murakami T;Ohshima H;Hayasaki H;Noguchi H
1型糖尿病的发生是由于胰岛中胰腺β细胞的自身免疫性破坏。胰岛移植是治疗1型糖尿病患者的一个有前途的选择，尽管最大限度的照顾，但经历低血糖无意识的患者，但目前供体胰岛的短缺阻碍了这种移植。移植来自患者自身的胰岛素产生细胞将是治愈1型糖尿病最有希望的方法之一。以前，我们证明了可以通过用Yamanaka重编程因子转染小鼠胰腺细胞来产生胰岛素产生细胞。非肥胖糖尿病（NOD）小鼠是由于胰腺β细胞的自身免疫消融而导致胰岛素产生缺陷的天然存在的突变小鼠。在这项研究中，我们表明，葡萄糖敏感的胰岛素生产细胞成功地产生的原代胰腺细胞从NOD小鼠（年龄6个月大）与质粒携带的cDNA为Oct-3/4，Sox 2，Klf 4，和c-Myc。以2天间隔重复转染4次。最终转染后65天，出现鹅卵石样集落。它们在体外增殖并表达多能性相关基因以及Pdx 1，Pdx 1是一种对β细胞谱系的组织特异性干细胞特异性的转录因子。与诱导多能干细胞（iPSC）不同，将这些细胞移植到裸鼠中未能产生畸胎瘤。将这些细胞诱导为胰腺β细胞谱系证明了它们响应于葡萄糖产生胰岛素的能力。这些发现表明，功能性胰腺β细胞可以从1型糖尿病患者中产生。我们将这些细胞称为“来自胰腺的诱导组织特异性干细胞”（iTS-P），这可能是1型糖尿病基于细胞治疗的安全有效材料的宝贵来源。
Type 1 diabetes occurs due to the autoimmune destruction of pancreatic β-cells in islets. Transplantation of islets is a promising option for the treatment of patients with type 1 diabetes that experience hypoglycemic unawareness despite maximal care, but the present shortage of donor islets hampers such transplantation. Transplantation of insulin-producing cells derived from the patients themselves would be one of the most promising approaches to cure type 1 diabetes. Previously, we demonstrated that insulin-producing cells could be produced by transfecting murine pancreatic cells with Yamanaka’s reprogramming factors. Non-obese diabetic (NOD) mice are naturally occurring mutant mice defective in insulin production due to autoimmune ablation of pancreatic β-cells. In this study, we showed that glucose-sensitive insulin-producing cells are successfully generated by transfecting primary pancreatic cells from NOD mice (aged 6 months old) with a plasmid harboring the cDNAs for Oct-3/4, Sox2, Klf4, and c-Myc. Transfection was repeated 4 times in a 2 day-interval. Sixty-five days after final transfection, cobblestone-like colonies appeared. They proliferated in vitro and expressed pluripotency-related genes as well as Pdx1, a transcription factor specific to tissue-specific stem cells for the β-cell lineage. Transplantation of these cells into nude mice failed to produce teratoma unlike induced pluripotent stem cells (iPSCs). Induction of these cells to the pancreatic β-cell lineage demonstrated their capability to produce insulin in response to glucose. These findings suggest that functional pancreatic β-cells can be produced from patients with type 1 diabetes. We call these resultant cells as “induced tissue-specific stem cells from the pancreas” (iTS-P) that could be valuable sources of safe and effective materials for cell-based therapy in type 1 diabetes.
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影响因子：
64.5
作者：
Park IH;Arora N;Huo H;Maherali N;Ahfeldt T;Shimamura A;Lensch MW;Cowan C;Hochedlinger K;Daley GQ
通讯作者：
Daley GQ
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