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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

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 1

Kinetics of hepatic repopulation.

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Kinetics of hepatic repopulation.
(A) Ad-HGF administration accelerated ...
(A) Ad-HGF administration accelerated repopulation. ROSA26 mouse hepatocytes (1 × 106) were transplanted into male PiZ mice without (upper row) or with (lower row) Ad-HGF (1 × 1011 particles, i.v.). Liver sections were stained for E. coli β-gal (blue), and diastase plus PAS (magenta) to visualize AAT-Z globules. Scale bars: 100 μm. Data are from representative mice from each group (n = 6). (B) Repopulation was greater in male recipients. Male and female PiZ mice received Ad-HGF (n = 6). Hepatocyte transplantation and staining of liver sections were as in A. (C and D) Quantitative DNA PCR. Quantitative PCR for the E. colilacZ gene was performed on DNA extracted from livers of recipient mice. Percentage of repopulation was calculated as described in the text. (C) Graphic presentation of data from experimental groups shown in A (mean ± SEM; n = 6 in each group), showing significantly higher repopulation in the Ad-HGF group at all time points (P < 0.05). (D) Data are from the experimental groups shown in B (mean ± SEM; n = 6 in each group), showing significantly higher repopulation in males 30, 60, and 90 days after transplantation (P < 0.05).
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