IsletTester小鼠：用于研究人类胰岛的具有稳定高血糖的免疫缺陷模型

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes Pub Date : 2024-11-21 DOI:10.2337/db23-0887

Eric L. Waite, Mark Tigue, Ming Yu, Deeksha Lahori, Kai Kelly, Catherine Lee May, Ali Naji, Jeffrey Roman, Nicolai Doliba, Dana Avrahami, Kim-Vy Nguyen-Ngoc, Maike Sander, Benjamin Glaser, Klaus H. Kaestner

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引用次数: 0

摘要

评估从干细胞中提取的人类胰岛或β样细胞功能的黄金标准是将其移植到高血糖免疫缺陷小鼠的肾囊下。目前的模型，如用链脲佐菌素（STZ）治疗严重免疫缺陷小鼠或NRG-Akita品系小鼠，由于这些模型的高血糖不稳定且可变，以及/或发病率高而受到限制。为了解决这些局限性，我们通过 CRISPR-Cas9 介导的基因编辑，直接在 NSG 子代中编辑葡萄糖激酶（Gck）（β 细胞的葡萄糖传感器），从而开发出 IsletTester 小鼠。IsletTester小鼠是Gck中Arg345->stop突变的杂合子，具有稳定的随机高血糖（250mg/dl; ∼ 14 mM）、正常寿命和生育能力。我们通过人类胰岛和 hESC 衍生的β样细胞的功能性移植证明了该模型的实用性。IsletTester小鼠可以在不同的生理条件下对人类胰岛生物学进行长期研究，并为确定干细胞衍生胰岛产品的功能性提供了一个有用的临床前平台。

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The IsletTester mouse: an immunodeficient model with stable hyperglycemia for the study of human islets

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.

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.