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

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.

A universal system to select gene-modified hepatocytes in vivo

“…It is known that hepatocytes can be massively selected in vivo in both mice and humans, in settings where the host liver has a genetic disadvantage (16). Gene-corrected hepatocytes have a selective advantage in Wilsons disease (17), α1-antitrypsin deficiency (18), progressive familial intrahepatic cholestasis (19), and hereditary tyrosinemia (16, 20). These rare examples highlight the inherent regenerative capacity of mature hepatocytes.…”

Bile Duct Ligation Induces ATZ Globule Clearance in a Mouse Model of α-1 Antitrypsin Deficiency

“…Frozen unfixed liver tissue sections (n=3) were stained with cresyl violet, and clusters of GC and GD cells were isolated via laser capture microdissection (LCM) for total RNA isolation, as described 8 . Gene array analysis of RNA expression was performed using Affymetrix mouse 2.0 ST arrays.…”

Characterization and use of HapT1-derived homologous tumors as a preclinical model to evaluate therapeutic efficacy of drugs against pancreatic tumor desmoplasia

“…Stained slides were observed under a Leica DM500 light microscope, and images were taken at 10× and 40× magnifications. The percentage of collagen stained area (aniline blue) was quantified using the automated ImageJ program in conjunction with the threshold plug-in [43]. …”