Role of hepatocyte direct hyperplasia in lentivirus-mediated liver transduction in vivo

Kazuo Ohashi, Frank Park, Mark A. Kay

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Lentiviral vectors have been used for gene transfer into the liver, but the ability of these vectors to efficiently transduce quiescent hepatocytes remains controversial. Regardless, lentivirus-mediated gene transfer is greatly enhanced when delivered during hepatocellular cycling. For this reason, the present study was designed to determine the role of hepatocyte proliferation in the enhancement of lentiviral transduction by using three different modes of liver regeneration: (1) compensatory regeneration stimulated by two-thirds partial hepatectomy, (2) direct hyperplasia after intragastric administration of the primary mitogen 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), and (3) a combination of modes 1 and 2. Vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped lentiviral vector expressing β-galactosidase was administered to mice via the peripheral circulation after a regeneration stimulus. Gene transfer as measured by 5-bromo-4-chloro-3-indolyl-β-D-galactoside (X-Gal) staining showed 30-fold higher levels of liver transduction in groups 1 and 2 as compared with the non-liver-manipulated control group (p < 0.005). The combination of TCPOBOP and partial hepatectomy (group 3) resulted in an ∼80-fold increase in transduction efficiency compared with the control animals. The enhanced transduction was consistent with higher levels of hepatocellular proliferation observed in animals that received both treatments compared with either single treatment alone. Importantly, the hepatocytes were the predominant cell type transduced, although transgene expression was observed in a low number of nonparenchymal cells regardless of which liver stimulus was received. Biodistribution studies confirmed that most of the gene transfer was limited to the liver and spleen. Taken together, this study suggests that disease-induced cellular proliferation in the liver will enhance the utility of this vector in treating diseases such as viral hepatitis, liver cirrhosis, and cancer.

Original languageEnglish (US)
Pages (from-to)653-663
Number of pages11
JournalHuman Gene Therapy
Volume13
Issue number5
DOIs
StatePublished - Apr 10 2002

Fingerprint

Lentivirus
Hyperplasia
Hepatocytes
Liver
Hepatectomy
Genes
Regeneration
Galactosidases
Galactosides
Vesicular Stomatitis
Liver Regeneration
Liver Neoplasms
Transgenes
Mitogens
Liver Cirrhosis
Hepatitis
Glycoproteins
Spleen
Cell Count
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Role of hepatocyte direct hyperplasia in lentivirus-mediated liver transduction in vivo. / Ohashi, Kazuo; Park, Frank; Kay, Mark A.

In: Human Gene Therapy, Vol. 13, No. 5, 10.04.2002, p. 653-663.

Research output: Contribution to journalArticle

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