Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes
Open Access
- 2 May 2011
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 121 (5), 1930-1934
- https://doi.org/10.1172/jci45260
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.This publication has 17 references indexed in Scilit:
- An Autophagy-Enhancing Drug Promotes Degradation of Mutant α 1 -Antitrypsin Z and Reduces Hepatic FibrosisScience, 2010
- Bile salt-induced pro-oxidant liver damage promotes transplanted cell proliferation for correcting Wilson disease in the Long-Evans Cinnamon rat modelJournal of Hepatology, 2008
- Correction of Hyperoxaluria by Liver Repopulation With Hepatocytes in a Mouse Model of Primary Hyperoxaluria Type-1Transplantation, 2008
- Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse modelJournal of Hepatology, 2007
- Hepatocyte transplantationJournal of Hepatology, 2004
- Drosophila Myc Regulates Organ Size by Inducing Cell CompetitionCell, 2004
- Analyses of hepatocellular proliferation in a mouse model of α-1-antitrypsin deficiencyJournal of Hepatology, 2004
- Principles of Therapeutic Liver RepopulationSeminars in Liver Disease, 1999
- The mechanism of Z α1-antitrypsin accumulation in the liverNature, 1992
- Alpha 1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis and strategies for therapy.JCI Insight, 1990