Generation of mouse models for type 1 diabetes by selective depletion of pancreatic beta cells using toxin receptor-mediated cell knockout
Generation of mouse models for type 1 diabetes by selective depletion of pancreatic beta cells using toxin receptor-mediated cell knockout
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DOI：
10.1016/j.bbrc.2013.05.114
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发表时间：
2013-07-05
影响因子：
3.1
通讯作者：
Yonekawa, Hiromichi
中科院分区：
文献类型：
--
作者：
Matsuoka, Kunie;Saito, Michiko;Yonekawa, Hiromichi
通过使用毒素受体介导的细胞敲除（TRECK）的方法，我们已经产生了两个转基因（Tg）小鼠系模型I型（胰岛素依赖型）糖尿病。第一个菌株C. B-17/Icr-Prkdc（scid）/Prkdc（scid）-INS-TRECK-Tg携带由人胰岛素基因启动子驱动的白喉毒素受体（hDTR），而另一个菌株C57 BL/6-ins2（BAC）-TRECK-Tg在小鼠胰岛素II基因启动子的控制下表达hDTR cDNA。关于C. B-17/Icr-Prkdc（scid）/Prkdc（scid）-INS-TRECK-Tg菌株，三种Tg菌株中只有一种在胰腺13细胞中表现出hDTR的适当表达。相比之下，hDTR在所有四种产生的C57BL/6-ins2（BAC）-TRECK-Tg菌株的胰腺β细胞中表达。在这些Tg小鼠中给予白喉毒素（DT）后3天内观察到高血压、胰腺β细胞的严重消融和血清胰岛素的耗竭。皮下注射适当剂量的胰岛素足以使所有受检菌株从高血糖中恢复。本研究以C. B-17/Icr-Prkdc（scid）/Prkdc（scid）-INS-TRECK-Tg模型为研究对象，尝试了C57 BL/6胰岛细胞同种异体移植和CD34（+）人脐带血细胞异种移植两种再生治疗方法。两种方法都成功地将C. B-17/Icr-Prkdc（scid）/Prkdc（scid）-INS-TRECK-Tg小鼠从DT给药引起的高血糖症中解救出来。DT导致这些Tg小鼠的胰腺β细胞消耗的高特异性对于糖尿病研究非常有用。(C)2013作者爱思唯尔公司出版All rights reserved.
By using the toxin receptor-mediated cell knockout (TRECK) method, we have generated two transgenic (Tg) murine lines that model type I (insulin-dependent) diabetes. The first strain, C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg, carries the diphtheria toxin receptor (hDTR) driven by the human insulin gene promoter, while the other strain, C57BL/6-ins2(BAC)-TRECK-Tg, expresses hDTR cDNA under the control of the mouse insulin II gene promoter. With regard to the C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg strain, only one of three Tg strains exhibited proper expression of hDTR in pancreatic 13 cells. By contrast, hDTR was expressed in the pancreatic beta cells of all four of the generated C57BL/6-ins2(BAC)-TRECK-Tg strains. Hyperglycemia, severe ablation of pancreatic beta cells and depletion of serum insulin were observed within 3 days after the administration of diphtheria toxin (DT) in these Tg mice. Subcutaneous injection of a suitable dosage of insulin was sufficient for recovery from hyperglycemia in all of the examined strains. Using the C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg model, we tried to perform regenerative therapeutic approaches: allogeneic transplantation of pancreatic islet cells from C57BL/6 and xenogeneic transplantation of CD34(+) human umbilical cord blood cells. Both approaches successfully rescued C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg mice from hyperglycemia caused by DT administration. The high specificity with which DT causes depletion in pancreatic beta cells of these Tg mice is highly useful for diabetogenic research. (C) 2013 The Authors. Published by Elsevier Inc. All rights reserved.