Format

Send to

Choose Destination
Mol Genet Metab. 2018 Jun;124(2):114-123. doi: 10.1016/j.ymgme.2018.04.005. Epub 2018 Apr 21.

Human hepatocyte transplantation corrects the inherited metabolic liver disorder arginase deficiency in mice.

Author information

1
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
2
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
3
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
4
Behavioral Testing Core Facility, Department of Psychology and Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
5
Department of Psychiatry, The David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States.
6
Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Molecular Biology Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Psychiatry, The David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Intellectual and Developmental Disabilities Research Center at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Semel Institute for Neuroscience, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; Broad Center for Regenerative Medicine and Stem Cell Research at UCLA, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. Electronic address: glipshutz@mednet.ucla.edu.

Abstract

The transplantation, engraftment, and expansion of primary hepatocytes have the potential to be an effective therapy for metabolic disorders of the liver including those of nitrogen metabolism. To date, such methods for the treatment of urea cycle disorders in murine models has only been minimally explored. Arginase deficiency, an inherited disorder of nitrogen metabolism that presents in the first two years of life, has the potential to be treated by such methods. To explore the potential of this approach, we mated the conditional arginase deficient mouse with a mouse model deficient in fumarylacetoacetate hydrolase (FAH) and with Rag2 and IL2-Rγ mutations to give a selective advantage to transplanted (normal) human hepatocytes. On day -1, a uroplasminogen-expressing adenoviral vector was administered intravenously followed the next day with the transplantation of 1 × 106 human hepatocytes (or vehicle alone) by intrasplenic injection. As the initial number of administered hepatocytes would be too low to prevent hepatotoxicity-induced mortality, NTBC cycling was performed to allow for hepatocyte expansion and repopulation. While all control mice died, all except one human hepatocyte transplanted mice survived. Four months after hepatocyte transplantation, 2 × 1011 genome copies of AAV-TBG-Cre recombinase was administered IV to disrupt endogenous hepatic arginase expression. While all control mice died within the first month, human hepatocyte transplanted mice did well. Ammonia and amino acids, analyzed in both groups before and after disruption of endogenous arginase expression, while well-controlled in the transplanted group, were markedly abnormal in the controls. Ammonium challenging further demonstrated the durability and functionality of the human repopulated liver. In conclusion, these studies demonstrate that human hepatocyte repopulation in the murine liver can result in effective treatment of arginase deficiency.

KEYWORDS:

Ammonia; Arginase deficiency; Cellular transplant; Hyperargininemia; Treatment; Urea cycle disorder

PMID:
29724658
PMCID:
PMC5976549
[Available on 2019-06-01]
DOI:
10.1016/j.ymgme.2018.04.005

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center