The IsletTester Mouse: An Immunodeficient Model With Stable Hyperglycemia for the Study of Human Islets

Area of Science:

• * Diabetes research
• * Stem cell biology
• * Mouse models

Background:

• * Current mouse models for assessing human islet function in vivo exhibit unstable hyperglycemia and high morbidity.
• * Existing models limit the reliable evaluation of stem cell-derived beta-like cells.
• * There is a need for improved preclinical models for islet transplantation and cell therapy.

Purpose of the Study:

• * To develop a novel, stable hyperglycemic mouse model for assessing human islet and stem cell-derived beta-like cell function.
• * To overcome the limitations of existing mouse models, including variable hyperglycemia and high morbidity.
• * To establish a reliable preclinical platform for evaluating the efficacy of islet transplantation and cell therapies.

Main Methods:

• * CRISPR/Cas9 gene editing was used to introduce a glucokinase (Gck) mutation in NSG zygotes.
• * The resulting IsletTester mice are heterozygous for an Arg345→stop Gck mutation.
• * Functional assessment involved engraftment of human islets and human embryonic stem cell-derived beta-like cells.

Main Results:

• * IsletTester mice exhibit stable, moderate random hyperglycemia (approximately 250 mg/dL).
• * These mice have a normal lifespan and fertility, unlike current models.
• * Engraftment of human islets and stem cell-derived beta-like cells demonstrated functional correction of hyperglycemia.

Conclusions:

• * The IsletTester mouse is a robust and reliable model for in vivo assessment of human islet and stem cell-derived beta-like cell function.
• * This model provides a valuable preclinical platform for studying human islet biology and evaluating cell therapies for diabetes.
• * The IsletTester mouse overcomes key limitations of existing models, enabling more accurate and consistent research outcomes.