title: 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.
authors.affiliation: Department of Medicine and Department of Genetics, Albert Einstein College of Medicine, New York, NY, USA.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Ding
authors.forename: Govardhana R
authors.initials: GR
authors.lastname: Yannam
authors.forename: Namita
authors.initials: N
authors.lastname: Roy-Chowdhury
authors.forename: Tunda
authors.initials: T
authors.lastname: Hidvegi
authors.forename: Hesham
authors.initials: H
authors.lastname: Basma
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Wong
authors.forename: Yesim
authors.initials: Y
authors.lastname: Avsar
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
authors.forename: David H
authors.initials: DH
authors.lastname: Perlmutter
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
authors.forename: Jayanta
authors.initials: J
authors.lastname: Roy-Chowdhury
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000418:Albumins / Q000378:metabolism; D000818:Animals; D001663:Bilirubin / Q000737:chemistry; D005355:Fibrosis / Q000378:metabolism; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D019076:Transgenes; D014184:Transplantation, Homologous; D000515:alpha 1-Antitrypsin / Q000235:genetics*
chemical_list: D000418:Albumins; D000515:alpha 1-Antitrypsin; D000410:Alanine Transaminase; D001663:Bilirubin