Extensive double humanization of both liver and hematopoiesis in FRGN mice

Elizabeth M. Wilson, J. Bial, G. Bial, B. Jensen, D. L. Greiner, M. A. Brehm, Markus Grompe

Research output: Contribution to journalArticle

66 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)404-412
Number of pages9
JournalStem Cell Research
Issue numberPart A
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

Fingerprint

Hematopoiesis
Liver
Hepatocytes
Hematopoietic Stem Cells
Busulfan
Alcoholic Liver Diseases
Chimerism
Kupffer Cells
Fatty Liver
Hepatitis C
Infection
Coinfection
HIV Infections
Liver Diseases
Blood Cells
Transplantation
Bone Marrow
Macrophages
Inflammation
Wounds and Injuries

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Medicine(all)

Cite this

Wilson, E. M., Bial, J., Bial, G., Jensen, B., Greiner, D. L., Brehm, M. A., & Grompe, M. (2014). Extensive double humanization of both liver and hematopoiesis in FRGN mice. Stem Cell Research, (Part A), 404-412. https://doi.org/10.1016/j.scr.2014.08.006

Extensive double humanization of both liver and hematopoiesis in FRGN mice. / Wilson, Elizabeth M.; Bial, J.; Bial, G.; Jensen, B.; Greiner, D. L.; Brehm, M. A.; Grompe, Markus.

In: Stem Cell Research, No. Part A, 01.11.2014, p. 404-412.

Research output: Contribution to journalArticle

Wilson, EM, Bial, J, Bial, G, Jensen, B, Greiner, DL, Brehm, MA & Grompe, M 2014, 'Extensive double humanization of both liver and hematopoiesis in FRGN mice', Stem Cell Research, no. Part A, pp. 404-412. https://doi.org/10.1016/j.scr.2014.08.006
Wilson EM, Bial J, Bial G, Jensen B, Greiner DL, Brehm MA et al. Extensive double humanization of both liver and hematopoiesis in FRGN mice. Stem Cell Research. 2014 Nov 1;(Part A):404-412. https://doi.org/10.1016/j.scr.2014.08.006
Wilson, Elizabeth M. ; Bial, J. ; Bial, G. ; Jensen, B. ; Greiner, D. L. ; Brehm, M. A. ; Grompe, Markus. / Extensive double humanization of both liver and hematopoiesis in FRGN mice. In: Stem Cell Research. 2014 ; No. Part A. pp. 404-412.
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