Original ResearchBasic and Translational—LiverDeactivation of Hepatic Stellate Cells During Liver Fibrosis Resolution in Mice
Section snippets
Generation of Vimentin-CreER Mice
A CreERFrtNeoFrt cassette was PCR-amplified from a p451 plasmid14 with 60-bp overhangs homologous to the upstream and downstream sequence surrounding ATG site of the mouse vimentin gene. The PCR product was inserted into a BAC containing the mouse vimentin gene by recombineering. After removal of the Neo cassette by arabinose-induced flippase, BAC DNA was microinjected into the pronucleus of fertilized CBA×C57BL/6J oocytes. One of 3 founders showed strong Vimentin-CreER (Vim-CreER) activity
Activation of HSCs in the Injured Liver at a Single-Cell Level
To determine whether activated HSCs can deactivate, we first compared fibrogenic gene expression in CCl4-injured livers and HSCs at different time points after cessation of injury to pre- and peak-injury levels. After 4 injections of CCl4, fibrogenic gene expression in whole liver was elevated 2 days after the last injection, and gradually returned to normal levels with almost normalized levels of fibrogenic gene expression 30 days after the last CCl4 injection (Figure 1A). This regimen also
Discussion
Removal of hepatic myofibroblasts by apoptosis is considered the key mechanism that reduces the number of activated myofibroblasts and allows the liver to return to normal architecture.6 Here we provide evidence that reversal of hepatic myofibroblasts to a quiescent state represents a second mechanism that contributes to the regression of liver fibrosis. Our study used 2 complementary approaches, single-cell qPCR and genetic cell fate tracking, to determine reversal of activated HSCs to a
Conclusion
Our study shows deactivation of roughly half the HSC population during liver fibrosis regression and higher responsiveness of reverted HSCs to recurrent profibrogenic stimulation.
Acknowledgments
Juliane S. Troeger and Ingmar Mederacke contributed equally to this study.
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Conflicts of interest The authors disclose no conflicts.
Funding This study was supported by grants R01DK076920 (to RFS), U54CA1261513 (PI of Project 2: RFS), and U54CA163111. Ingmar Mederacke was supported by the German Research Foundation (ME 3723/1-1). Dianne Dapito was supported by 1F31DK091980. Jean-Philippe Pradere was supported by a postdoctoral fellowship from the American Liver Foundation.