An inducible model for genetic manipulation and fate-tracing of PDGFRβ-expressing fibrogenic cells in the liver

Abstract

Myofibroblasts are the source of extracellular matrix protein during liver fibrogenesis. Fibroblasts, hepatic stellate cells (HSCs) and vascular smooth muscle cells are mesenchymal subpopulations in the liver that are characterized by the expression of PDGFRβ and contribute to the pool of these myofibroblasts. Conditional knockout models are important to better understand the function of specific liver cell populations including mesenchymal cells. While there is a limited number of constitutive mouse models for liver mesenchymal cell specific transgene expression, there is no established model for inducible gene targeting in HSCs or PDGFRβ-expressing mesenchymal cell populations in the liver. To address this, we investigated whether the tamoxifen inducible PDGFRβ-P2A-CreERT2 mouse can be used as a reliable tool to specifically express transgens in liver mesenchymal cells. Our data demonstrate, that PDGFRβ-P2A-CreERT2 specifically and efficiently marks over 90% of retinoid positive HSCs in healthy and fibrotic liver in mice upon tamoxifen injection, and that those cells give rise to Col1a1-expressing myofibroblasts in different models of liver fibrosis. Together with a negligible background recombination of only about 0.33%, this confirms that the PDGFRβ-P2A-CreERT2 mouse is nearly as efficient as established constitutive LratCre and PDGFRβ-Cre mouse models for recombination in HSCs, and that it is a powerful model for mesenchymal liver cell studies that require an inducible Cre approach.