Elsevier

Stem Cell Research

Volume 13, Issue 3, Part A, November 2014, Pages 404-412
Stem Cell Research

Extensive double humanization of both liver and hematopoiesis in FRGN mice

https://doi.org/10.1016/j.scr.2014.08.006Get rights and content
Under a Creative Commons license
open access

Highlights

  • First protocol to make mice highly chimeric for both human hepatocytes and blood

  • Model for interactions between human inflammatory cells and human hepatocytes

  • Humanized niche for human hematopoietic stem cells

  • Human Kupffer cells were found in humanized liver.

  • Human lymphocytes were found in humanized liver.

Abstract

Preclinical research in animals often fails to adequately predict the outcomes observed in human patients. Chimeric animals bearing individual human tissues have been developed to provide improved models of human-specific cellular processes. Mice transplanted with human hematopoietic stem cells can be used to study human immune responses, infections of blood cells and processes of hematopoiesis. Animals with humanized livers are useful for modeling hepatotropic infections as well as drug metabolism and hepatotoxicity. However, many pathophysiologic processes involve both the liver and the hematolymphoid system. Examples include hepatitis C/HIV co-infection, immune mediated liver diseases, liver injuries with inflammation such as steatohepatitis and alcoholic liver disease.

We developed a robust protocol enabling the concurrent double-humanization of mice with mature hepatocytes and human blood. Immune-deficient, fumarylacetoacetate hydrolase (Fah−/−), Rag2−/− and Il2rg−/− deficient animals on the NOD-strain background (FRGN) were simultaneously co-transplanted with adult human hepatocytes and hematopoietic stem cells after busulfan and Ad:uPA pre-conditioning. Four months after transplantation the average human liver repopulation exceeded 80% and hematopoietic chimerism also was high (40–80% in bone marrow). Importantly, human macrophages (Kupffer cells) were present in the chimeric livers.

Double-chimeric FRGN mice will serve as a new model for disease processes that involve interactions between hepatocytes and hematolymphoid cells.

Cited by (0)

This work was supported by NIH SBIR 1R43OD010563-01A1 grant to E. M. W. and AI046629 to D. L. G. and M. A. B.