+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

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



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



Journal of Clinical Investigation 121(5): 1930-1934



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.

(PDF emailed within 1 workday: $29.90)

Accession: 055889581

Download citation: RISBibTeXText

PMID: 21505264


Related references

No dopamine cell loss or changes in cytoskeleton function in transgenic mice expressing physiological levels of wild type or G2019S mutant LRRK2 and in human fibroblasts. Plos One 10(4): E0118947, 2015

Donor hepatocytes have a selective repopulation advantage over host hepatocytes in Alpha I-antitrypsin deficiency. 2007

Elevated synthesis of human a1-antitrypsin hinders the secretion of murine a1-antitrypsin from hepatocytes of transgenic mice. The Journal of Biological Chemistry 264: 696-700, 1989

Spontaneous generation of rapidly transmissible prions in transgenic mice expressing wild-type bank vole prion protein. Proceedings of the National Academy of Sciences of the United States of America 109(9): 3498-3503, 2012

Toxicity studies with 5-hydroxymethylfurfural and its metabolite 5-sulphooxymethylfurfural in wild-type mice and transgenic mice expressing human sulphotransferases 1A1 and 1A2. Archives of Toxicology 86(5): 701-711, 2012

Transgenic mice expressing a mutant human GH gene causing type II IGHD. Environmental Medicine 46(1-2): 36-39, 2002

Changes in dendritic complexity and spine morphology in transgenic mice expressing human wild-type tau. Brain Structure and Function 214(2-3): 161-179, 2010

The neuronal Golgi apparatus is fragmented in transgenic mice expressing a mutant human SOD1, but not in mice expressing the human NF-H gene. Journal of the Neurological Sciences 173(1): 63-72, Feb 1, 2000

Over-expression of wild-type and a mutant human p53 in the lens of transgenic mice. Journal of Cellular Biochemistry Supplement 0(21A): 341, 1995

Study of 5-hydroxymethylfurfural and its metabolite 5-sulfooxymethylfurfural on induction of colonic aberrant crypt foci in wild-type mice and transgenic mice expressing human sulfotransferases 1A1 and 1A2. Molecular Nutrition and Food Research 56(4): 593-600, 2012

Elevated synthesis of human alpha 1-antitrypsin hinders the secretion of murine alpha 1-antitrypsin from hepatocytes of transgenic mice. Journal of Biological Chemistry 264(26): 15696-15700, 1989

Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins. Journal of General Virology 90(Pt 3): 546-558, 2009

Formation of DNA adducts in wild-type and transgenic mice expressing human sulfotransferases 1A1 and 1A2 after oral exposure to furfuryl alcohol. Mutagenesis 30(5): 643-649, 2016

Inhibitors of Cathepsin B Improve Memory and Reduce b-Amyloid in Transgenic Alzheimer Disease Mice Expressing the Wild-type, but Not the Swedish Mutant, b-Secretase Site of the Amyloid Precursor Protein. 2008