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).
Li
Zong-Yi
ZY
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington 98195, USA.
Otto
Kevin
K
Richard
Robert E
RE
Ni
Shaoheng
S
Kirillova
Irina
I
Fausto
Nelson
N
Blau
C Anthony
CA
Lieber
André
A
D000818:Animals; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D019281:Dimerization; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D022781:Hepatocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008251:Macaca; D051379:Mice; D012190:Retroviridae / Q000235:genetics; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology*
C463061:AP20187; D016559:Tacrolimus