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.
