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Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes
Jianqiang Ding, … , Ira J. Fox, Jayanta Roy-Chowdhury
Jianqiang Ding, … , Ira J. Fox, Jayanta Roy-Chowdhury
Published April 18, 2011
Citation Information: J Clin Invest. 2011;121(5):1930-1934. https://doi.org/10.1172/JCI45260.
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Brief Report Hepatology Article has an altmetric score of 10

Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes

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Abstract

α1-Antitrypsin deficiency is an inherited condition that causes liver disease and emphysema. The normal function of this protein, which is synthesized by the liver, is to inhibit neutrophil elastase, a protease that degrades connective tissue of the lung. In the classical form of the disease, inefficient secretion of a mutant α1-antitrypsin protein (AAT-Z) results in its accumulation within hepatocytes and reduced protease inhibitor activity, resulting in liver injury and pulmonary emphysema. Because mutant protein accumulation increases hepatocyte cell stress, we investigated whether transplanted hepatocytes expressing wild-type AAT might have a competitive advantage relative to AAT-Z–expressing hepatocytes, using transgenic mice expressing human AAT-Z. Wild-type donor hepatocytes replaced 20%–98% of mutant host hepatocytes, and repopulation was accelerated by injection of an adenovector expressing hepatocyte growth factor. Spontaneous hepatic repopulation with engrafted hepatocytes occurred in the AAT-Z–expressing mice even in the absence of severe liver injury. Donor cells replaced both globule-containing and globule-devoid cells, indicating that both types of host hepatocytes display impaired proliferation relative to wild-type hepatocytes. These results suggest that wild-type hepatocyte transplantation may be therapeutic for AAT-Z liver disease and may provide an alternative to protein replacement for treating emphysema in AAT-ZZ individuals.

Authors

Jianqiang Ding, Govardhana R. Yannam, Namita Roy-Chowdhury, Tunda Hidvegi, Hesham Basma, Stephen I. Rennard, Ronald J. Wong, Yesim Avsar, Chandan Guha, David H. Perlmutter, Ira J. Fox, Jayanta Roy-Chowdhury

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Figure 2

Depletion of hepatic human AAT-Z content and restoration of normal liver histology after repopulation.

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Depletion of hepatic human AAT-Z content and restoration of normal liver...
(A) Male and female PiZ mice were transplanted with ROSA26 hepatocytes, with or without Ad-HGF administration (n = 6 in each group). Liver tissues were obtained by biopsy before and at various time points after transplantation and at the termination of the experiment. Hepatic human AAT-Z content was determined by Western blot/densitometry. Data (percentage of pretransplant values) are plotted against percentage of residual β-gal–negative host hepatocytes. The line of best fit is shown. (B) H&E staining of liver paraffin section after extensive (80%) hepatic repopulation by donor hepatocytes. (C–E) Masson’s trichrome–stained liver sections. (F–H) Sirius red–stained liver sections. (C and F) C57BL/6 mice; (D and G) untreated PiZ mice. (E and F) PiZ mice after 80% hepatic repopulation with wild-type hepatocytes. In Masson’s trichrome–stained sections, the area occupied by blue-stained collagen was quantified using the ImageJ program in conjunction with the Threshold Color plug-in. Scale bars: 100 μm.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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