Abstract
Chronic liver diseases are associated with excessive deposition of extracellular matrix proteins. This so-called fibrosis can progress to cirrhosis and impair vital functions of the liver. We examined whether the receptor tyrosine kinase (RTK) class III inhibitor Crenolanib affects the behavior of hepatic stellate cells (HSC) involved in fibrogenesis. Rats were treated with thioacetamide (TAA) for 18 weeks to trigger fibrosis. After TAA treatment, the animals received Crenolanib for two weeks, which significantly improved recovery from liver fibrosis. Because Crenolanib predominantly inhibits the RTK platelet-derived growth factor receptor-β, impaired HSC proliferation might be responsible for this beneficial effect. Interestingly, blocking of RTK signaling by Crenolanib not only hindered HSC proliferation but also triggered their specification into hepatic endoderm. Endodermal specification was mediated by p38 mitogen-activated kinase (p38 MAPK) and c-Jun-activated kinase (JNK) signaling; however, this process remained incomplete, and the HSC accumulated lipids. JNK activation was induced by stress response-associated inositol-requiring enzyme-1α (IRE1α) in response to Crenolanib treatment, whereas β-catenin-dependent WNT signaling was able to counteract this process. In conclusion, the Crenolanib-mediated inhibition of RTK impeded HSC proliferation and triggered stress responses, initiating developmental processes in HSC that might have contributed to improved recovery from liver fibrosis in TAA-treated rats.
Highlights
Our studies have demonstrated that hepatic stellate cells (HSC) are producers of extracellular matrix proteins and exhibit the expression pattern and functional characteristics of mesenchymal stem cells (MSC), which becomes apparent when they are activated [1,2,3,4]
We examined whether the receptor tyrosine kinase (RTK) class III inhibitor Crenolanib affects the behavior of hepatic stellate cells (HSC) involved in fibrogenesis
Rats were treated with TAA via drinking water for 18 weeks to initiate liver fibrosis, which was confirmed by the nodular appearance of the organ surface (Figure 1A,B)
Summary
Our studies have demonstrated that hepatic stellate cells (HSC) are producers of extracellular matrix proteins and exhibit the expression pattern and functional characteristics of mesenchymal stem cells (MSC), which becomes apparent when they are activated [1,2,3,4]. HSC are associated with sinusoidal endothelial cells and located in the space of Disse, which constitutes their perivascular stem cell niche between endothelial cells and hepatocytes [4,17,18]. This niche preserves the quiescent state of HSC, which is characterized by the presence of retinoid-containing vesicles [19,20,21]. HSC become activated, lose their retinoids, and develop into myofibroblast-like cells, which contribute to fibrosis during chronic liver diseases through the deposition of extracellular matrix proteins [22] that affect vital liver functions
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