The receptor tyrosine kinase inhibitor Crenolanib improves recovery from liver fibrosis in thioacetamide-treated rats

Platelet-derived growth factor receptor (PDGFR)-mediated signaling induces proliferation of stellate cells, which contributes to fibrogenesis in chronic liver diseases. Since PDGF levels increase in the blood of patients with fibrotic liver, we addressed the question of whether interfering with PDGFR signaling improves recovery from this disease. To induce fibrous scars in liver tissue, rats were treated with thioacetamide (TAA) for 18 weeks via the drinking water. After cessation of TAA administration, the animals received Crenolanib, which is a benzamidazole derivate capable to inhibit receptor tyrosine kinases (RTK) of class III such as PDGFR-α/β, FMS related tyrosine kinase-3 (FLT3), and c-KIT. Administration of 0.05 mg/ml Crenolanib via the drinking water for 2 weeks significantly improved the recovery of the liver from TAA-induced fibrosis. Crenolanib-treated rats showed a clear regression of nodular appearance, macroscopically visible in fibrotic livers. Moreover, histological analyses of liver sections from these rats showed a significant decrease of Sirius Red staining and of collagen type IV, α-smooth muscle actin, PDGFR-β, and cytokeratin 19 immunofluorescence. Reestablishment of liver zonation, which disappeared during fibrosis, has also been observed in the presence of Crenolanib since glutamine synthetase-expressing hepatocytes reappeared close to blood vessels associated with scar residues. To elucidate the effects exerted by Crenolanib on the fibrotic liver, isolated hepatic stellate cells were treated with 0.1 and 1 µM Crenolanib for 14 days. Crenolanib not only lowered proliferation but also initiated hepatic endoderm specification of stellate cells in a p38 mitogen-activated protein kinase and c-Jun-activated kinase-dependent manner. However, this developmental process remained incomplete, and the stellate cells accumulated lipids, which might be caused by stress-responsive signaling pathways. Inhibition of cell proliferation and activation of a stress response that initiated developmental processes in stellate cells provide explanations for the improved recovery of Crenolanib-treated rats from liver fibrosis.