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

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1930-1934
Number of pages5
JournalJournal of Clinical Investigation
Volume121
Issue number5
DOIs
StatePublished - May 2 2011

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Transgenic Mice
Hepatocytes
Liver
Emphysema
Liver Diseases
Pulmonary Emphysema
Leukocyte Elastase
Hepatocyte Growth Factor
Wounds and Injuries
Mutant Proteins
Protease Inhibitors
Connective Tissue
Proteins
Peptide Hydrolases
Transplantation
Lung
Injections

ASJC Scopus subject areas

  • Medicine(all)

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Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes. / Ding, Jianqiang; Yannam, Govardhana R.; Roy-Chowdhury, Namita; Hidvegi, Tunda; Basma, Hesham; Rennard, Stephen I.; Wong, Ronald J.; Avsar, Yesim; Guha, Chandan; Perlmutter, David H.; Fox, Ira J.; Roy-Chowdhury, Jayanta.

In: Journal of Clinical Investigation, Vol. 121, No. 5, 02.05.2011, p. 1930-1934.

Research output: Contribution to journalArticle

Ding, J, Yannam, GR, Roy-Chowdhury, N, Hidvegi, T, Basma, H, Rennard, SI, Wong, RJ, Avsar, Y, Guha, C, Perlmutter, DH, Fox, IJ & Roy-Chowdhury, J 2011, 'Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes', Journal of Clinical Investigation, vol. 121, no. 5, pp. 1930-1934. https://doi.org/10.1172/JCI45260
Ding, Jianqiang ; Yannam, Govardhana R. ; Roy-Chowdhury, Namita ; Hidvegi, Tunda ; Basma, Hesham ; Rennard, Stephen I. ; Wong, Ronald J. ; Avsar, Yesim ; Guha, Chandan ; Perlmutter, David H. ; Fox, Ira J. ; Roy-Chowdhury, Jayanta. / Spontaneous hepatic repopulation in transgenic mice expressing mutant human α1-antitrypsin by wild-type donor hepatocytes. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 5. pp. 1930-1934.
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