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Published on: May 13, 2016
Dimerizer-induced proliferation of genetically modified hepatocytes
Zong-Yi Li1, Kevin Otto, Robert E Richard
1Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Summary
A synthetic drug, AP20187, selectively expands retrovirally transduced hepatocytes in vivo. This drug-inducible expansion method offers potential for liver gene therapy and cell repopulation strategies.
Area of Science:
- Hepatology
- Molecular Biology
- Gene Therapy
Background:
- Stable gene transfer into hepatocytes via viral vectors remains a significant challenge.
- Cell expansion is crucial for effective gene therapy and liver repopulation.
Purpose of the Study:
- To develop a method for stimulating the expansion of retrovirally transduced hepatocytes.
- To investigate the potential of drug-inducible signaling pathways for hepatocyte proliferation.
Main Methods:
- Utilized a synthetic drug (AP20187) to activate fusion proteins with growth factor receptor signaling domains (gp130, c-met, EGF-R, mpl) in hepatocytes.
- Assessed hepatocyte cell cycle entry and mitosis upon drug activation.
- Evaluated the in vivo expansion of retrovirally transduced hepatocytes using AP20187 and gp130 signaling.
Main Results:
- Activation of gp130 and c-met signaling domains induced hepatocyte mitosis.
- AP20187 treatment led to transient proliferation of primary mouse hepatocytes expressing the gp130 fusion.
- Selective expansion (>2-fold) of retrovirally transduced hepatocytes was achieved in vivo via AP20187-activated gp130 signaling.
Conclusions:
- Drug-inducible activation of specific growth factor receptor signaling pathways can promote hepatocyte proliferation.
- This approach enables selective in vivo expansion of genetically modified hepatocytes.
- The findings suggest potential applications in liver gene transfer and cell-based therapies.
