The gold standard for assessing the function of human islets or β-like cells derived from stem cells involves their engraftment under the kidney capsule of hyperglycemic, immunodeficient mice. Current models, such as Streptozotocin (STZ) treatment of severely immunodeficient mice or the NRG-Akita strain are limited due to unstable and variable hyperglycemia and/or high morbidity of these models. To address these limitations, we developed the IsletTester mouse via CRISPR-Cas9 mediated gene editing of glucokinase (Gck), the glucose sensor of the β-cells, directly in NSG zygotes. IsletTester mice are heterozygous for an Arg345->stop mutation in Gck and present with stable random hyperglycemia (∼250mg/dl; ∼14 mM), normal life span and fertility. We demonstrate the utility of this model through functional engraftment of both human islets and hESC-derived β-like cells. The IsletTester mouse will enable the study of human islet biology over time and under different physiological conditions and can provide a useful preclinical platform to determine the functionality of stem cell-derived islet products.

中文翻译：

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IsletTester 小鼠：一种用于人胰岛研究的稳定高血糖免疫缺陷模型


评估源自干细胞的人胰岛或β样细胞功能的金标准涉及它们植入高血糖、免疫缺陷小鼠的肾包膜下。由于这些模型的不稳定和可变的高血糖和/或高发病率，目前的模型，例如链脲佐菌素 （STZ） 治疗严重免疫缺陷小鼠或 NRG-Akita 菌株，受到限制。为了解决这些限制，我们通过 CRISPR-Cas9 介导的葡萄糖激酶 （Gck） 基因编辑（β细胞的葡萄糖传感器）直接在 NSG 受精卵中开发了 IsletTester 小鼠。IsletTester 小鼠是 Gck 中 Arg345->stop 突变的杂合子，表现为稳定的随机高血糖 （∼250mg/dl;∼14 mM），寿命和生育能力正常。我们通过人胰岛和 hESC 衍生的 β 样细胞的功能性植入来证明该模型的实用性。IsletTester 小鼠将能够研究人类胰岛生物学随时间和不同生理条件的变化，并可以提供一个有用的临床前平台来确定干细胞来源的胰岛产品的功能。