# Immunogenicity of Human Stem Cell-Derived Beta Cells and Muscle Cells in Humanized Mice

> **NIH NIH R24** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $823,750

## Abstract

Development of human embryonic stem cells (ESCs) and human induced pluripotent stem cells (iPSCs)
has unleashed the potential of cellular therapy for a number of human diseases. Replacement therapies
using human stem cell-derived β (SC-β) and SC-myoblasts (the two cell types used in this project), and
multiple other stem cell derivatives are of interest to essentially all of the Institutes and Centers at NIH. To
avoid rejection, cell replacement therapies will require immune protection by encapsulation, provided
immune-evading properties, or given with immunosuppression. As the cell products are of human origin,
immunogenicity can't be tested in vivo using immunocompetent animal models due to potent xenograft
responses. One can test the cells for safety, efficacy, and immunogenicity in patients, which will be time
consuming, expensive, and potentially dangerous. Thus, a critical requirement for the translation of human
stem cell-based therapy to the clinic is the development of robust pre-clinical animal models for evaluation
of the efficacy, safety and importantly, immunogenicity of human cellular therapy. We propose to modify
NOD-scid IL2rgnull (NSG) models of human diabetes and muscle disease to permit development of robust
human immune systems. This will allow rapid preclinical evaluation of the function and immunogenicity of
human SC-β cells and SC-myoblasts (and SC-derived cells in other models under development). We have
documented that current models of NSG mice engrafted with human immune systems cannot fully reject
allogeneic human ESCs or SC-endothelial cells, and in preliminary studies, cannot reject human SC-β cells.
Our Scientific Premise is that the limited function of the engrafted human immune system in
humanized NSG mice is due to lack of organized structure in secondary lymphoid tissues. We have
observed that engraftment of newborn NSG mice with wildtype murine HSC will lead to the development of
lymph nodes and robust immune responses, suggesting that a lack of species-specific factors impede
lymphoid development in humanized NSG mice. In this multi-PI, multi-disciplinary team proposal, Aim 1 will
generate novel NSG mouse strains of diabetes and muscular disease that express human specific factors
that support lymphoid structure and human immune function. Aim 2 will engraft human SC-β cells and SC-
myoblasts into our unique humanized mouse models of diabetes and muscle disease to test for function
and immunogenicity. Aim 3 will provide these validated new strains to The Jackson Laboratory (JAX)
Biorepository for worldwide distribution. Our proposal takes advantage of powerful new technologies for
creating new models of humanized mice, and builds on our track record for generating, validating, and to
date, sharing through the JAX distribution network of 17 novel models of humanized NSG mice since 2005.
We believe that our innovative approaches, combined with our multi-disciplinary collaborative team will
ensure the development ...

## Key facts

- **NIH application ID:** 9990868
- **Project number:** 5R24OD026440-02
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Michael Allen Brehm
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $823,750
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990868

## Citation

> US National Institutes of Health, RePORTER application 9990868, Immunogenicity of Human Stem Cell-Derived Beta Cells and Muscle Cells in Humanized Mice (5R24OD026440-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990868. Licensed CC0.

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