Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Conditional Genetic Elimination of Hepatocyte Growth Factor in Mice Compromises Liver Regeneration after Partial Hepatectomy

Nejak-Bowen, K and Orr, A and Bowen, WC and Michalopoulos, GK (2013) Conditional Genetic Elimination of Hepatocyte Growth Factor in Mice Compromises Liver Regeneration after Partial Hepatectomy. PLoS ONE, 8 (3).

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (7MB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

Abstract

Hepatocyte growth factor (HGF) has been shown to be indispensable for liver regeneration because it serves as a main mitogenic stimulus driving hepatocytes toward proliferation. We hypothesized that ablating HGF in adult mice would have a negative effect on the ability of hepatocytes to regenerate. Deletion of the HGF gene was achieved by inducing systemic recombination in mice lacking exon 5 of HGF and carrying the Mx1-cre or Cre-ERT transgene. Analysis of liver genomic DNA from animals 10 days after treatment showed that a majority (70-80%) of alleles underwent cre-induced genetic recombination. Intriguingly, however, analysis by RT-PCR showed the continued presence of both unrecombined and recombined forms of HGF mRNA after treatment. Separation of liver cell populations into hepatocytes and non-parenchymal cells showed equal recombination of genomic HGF in both cell types. The presence of the unrecombined form of HGF mRNA persisted in the liver in significant amounts even after partial hepatectomy (PH), which correlated with insignificant changes in HGF protein and hepatocyte proliferation. The amount of HGF produced by stellate cells in culture was indirectly proportional to the concentration of HGF, suggesting that a decrease in HGF may induce de novo synthesis of HGF from cells with residual unrecombined alleles. Carbon tetrachloride (CCl4)-induced regeneration resulted in a substantial decrease in preexisting HGF mRNA and protein, and subsequent PH led to a delayed regenerative response. Thus, HGF mRNA persists in the liver even after genetic recombination affecting most cells; however, PH subsequent to CCl4 treatment is associated with a decrease in both HGF mRNA and protein and results in compromised liver regeneration, validating an important role of this mitogen in hepatic growth. © 2013 Nejak-Bowen et al.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Nejak-Bowen, Kknnst5@pitt.eduKNNST5
Orr, Aavo4@pitt.eduAVO4
Bowen, WCbowen@pitt.eduBOWEN
Michalopoulos, GKmichal@pitt.eduMICHAL
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorColeman, William B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 20 March 2013
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 8
Number: 3
DOI or Unique Handle: 10.1371/journal.pone.0059836
Schools and Programs: School of Medicine > Pathology
Refereed: Yes
Date Deposited: 08 Apr 2013 17:02
Last Modified: 15 Dec 2018 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/17884

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item