# Immune Compromised Zebrafish for Cell Transplantation

> **NIH NIH R24** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $171,227

## Abstract

Cell transplantation into immune compromised mice has transformed our understanding of human disease and
has been used extensively to assess regeneration, stem cell self-renewal, and cancer in the xenograft
transplantation setting. Despite their great utility, mouse models are not amenable to large-scale studies due
to high husbandry costs and do not easily facilitate direct visualization of engrafted cells at single cell resolution.
By contrast, zebrafish are inexpensive, can be reared in large numbers, and are amenable to large-scale
chemical genetic approaches where compounds can be added directly to the water. Moreover, optically-clear
immune-deficient zebrafish strains have permitted large-scale cell transplantation studies to dynamically image
fluorescent-labeled cells at single cell resolution. Despite these successes, more needs to be done to develop
immune compromised zebrafish as a robust and long-term xenograft cell transplantation model. The long-term
goal of this application is to develop a universal zebrafish transplantation model for engrafting a wide array of
regenerative and cancer cell types from zebrafish, mouse, and human. The overall objective of this application
is to provide new immune deficient zebrafish models for optimized allograft engraftment of regenerative tissues
and xenograft engraftment of human cancer, ES, iPS, and CD34+ cord blood cells. The rationale for our
research is that zebrafish blood development is highly conserved and that developing zebrafish transplantation
models has already led to unique understanding of regenerative stem cell processes and dynamic visualization
of new cell behaviors that drive cell growth. Aim 1 will develop compound mutant and humanized transgenic
zebrafish for optimized cell transplantation. We will develop new models that lack all T, B, and NK cells,
including mutants in the recently identified NK-lysin expressing cytotoxic blood cells and full loss-of-function
mutations in the rag2 gene, which is required for mature T and B cell function. We will also generate
humanized zebrafish that transgenically express factors that support elevated growth of human cells, including
the human “don’t eat me” signal inhibitory regulatory protein alpha (SIRPa) and human cytokines. Aim 2 will
utilize these models for assessing orthotopic and xenograft engraftment, identifying lines that have superior,
long-term engraftment of human cancer cell lines, ES and iPS cells, and CD34+ cord blood cells. Aim 3 will
refine a system for global distribution and rapid dissemination of mutant lines to the zebrafish, stem cell, and
regenerative medicine community. Our work is significant because it will develop a much-needed resource for
the community, facilitating the next generation of low-cost, high throughput cell transplantation models to
engraft a wide array of regenerative cell types. This work is expected to have a positive translational impact by
developing pre-clinical animal models that facilitate d...

## Key facts

- **NIH application ID:** 10454455
- **Project number:** 3R24OD016761-08S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** David Michael Langenau
- **Activity code:** R24 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $171,227
- **Award type:** 3
- **Project period:** 2013-08-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454455

## Citation

> US National Institutes of Health, RePORTER application 10454455, Immune Compromised Zebrafish for Cell Transplantation (3R24OD016761-08S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10454455. Licensed CC0.

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