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

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

doi:10.2337/db23-0887

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

Diabetes. 2024 Nov 21:db230887. doi: 10.2337/db23-0887. Online ahead of print.

Authors

Eric L Waite^{1

2}, Mark Tigue^{1

2}, Ming Yu^{1

3}, Deeksha Lahori^{1

2}, Kai Kelly^{1

2}, Catherine Lee May^{1

2}, Ali Naji^{1

3}, Jeffrey Roman^{1

4}, Nicolai Doliba^{1

4}, Dana Avrahami⁵, Kim-Vy Nguyen-Ngoc⁶, Maike Sander^{6

7}, Benjamin Glaser⁸, Klaus H Kaestner^{1

2}

Affiliations

¹ Institute of Diabetes, Obesity, and Metabolism, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104.
² Department of Genetics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104.
³ Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia 19104.
⁴ Department of Biochemistry and Biophysics, Perelman School of Medicine, The University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA, USA 19104.
⁵ Department of Endocrinology and Metabolism, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel; Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
⁶ Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ Max Delbruck Center, 13125 Berlin, Germany.
⁸ Department of Endocrinology and Metabolism, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel.

PMID: 39571094
DOI: 10.2337/db23-0887

Abstract

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.