Dimerizer-induced proliferation of genetically modified hepatocytes.

Stable gene transfer to the liver by viral vectors is inefficient. In an attempt to stimulate expansion of retrovirally transduced hepatocytes, we employed a synthetic drug (AP20187) that can reversibly dimerize and activate fusion proteins that contain a growth factor receptor signaling domain. Signaling domains derived from receptors for interleukin-6 (gp130), hepatocyte growth factor (c-met), epithelial growth factor (EGF-R), and thrombopoietin (mpl) triggered monkey hepatocytes to enter the cell cycle. However, mitosis occurred only upon activation of the gp130 and c-met signaling domains. Primary mouse hepatocytes expressing the gp130 fusion proliferated transiently in response to AP20187. AP20187-triggered activation of gp130 also stimulated the selective (>2-fold) expansion of retrovirally transduced hepatocytes in vivo, as shown by immunohistochemical staining and quantitative proviral DNA analysis. Drug-inducible in vivo expansion of genetically modified hepatocytes may have potential applications in hepatic gene transfer or in liver repopulation by transplanted hepatocytes or their progenitors. (c)2002 Elsevier Science (USA).