Abstract
Liver fibrosis is a wound healing process in response to chronic liver injury, which is characterized by the accumulation of extracellular collagen produced by Hepatic Stellate Cells (HSCs). This process involves cell cycle re-entry and proliferation of normally quiescent HSCs controlled by cyclins and associated cyclin-dependent kinases (Cdks). Cdk2 mediates the entry and progression through S-phase in complex with E-and A-type cyclins. We have demonstrated that cyclin E1 is essential for liver fibrogenesis in mice, but it is not known if this is dependent on Cdk2 or related Cdks. Here, we aimed to evaluate the benefit of the pan-Cdk inhibitor CR8 for treatment of liver fibrosis in vitro. CR8-treatment reduced proliferation and survival in immortalized HSC lines and in addition attenuated pro-fibrotic properties in primary murine HSCs. Importantly, primary murine hepatocytes were much more tolerant against the cytotoxic and anti-proliferative effects of CR8. We identified CR8 dosages mediating anti-fibrotic effects in primary HSCs without affecting cell cycle activity and survival in primary hepatocytes. In conclusion, the pharmacological pan-Cdk inhibitor CR8 restricts the pro-fibrotic properties of HSCs, while preserving proliferation and viability of hepatocytes at least in vitro. Therefore, CR8 and related drugs might be beneficial for the treatment of liver fibrosis.
Highlights
Initiation of liver fibrosis is a consequence of chronic liver injury induced for instance by chronic viral hepatitis, fatty liver disease or excessive alcohol consumption
Fluorescence-associated cell sorting (FACS) of CR8-treated GRX and LX-2 cells revealed a dose-dependent increase of cleaved poly (ADP-ribose)-polymerase 1 (PARP-1) in both cell lines (Figure 1c,d)
Liver fibrosis is a wound healing process in response to chronic liver injury, characterized by regenerative proliferation of hepatocytes and the accumulation of extracellular collagen produced by Hepatic Stellate Cells (HSCs) [4]
Summary
Initiation of liver fibrosis is a consequence of chronic liver injury induced for instance by chronic viral hepatitis, fatty liver disease or excessive alcohol consumption. Two cellular events take place during initiation and progression of liver fibrosis, which are in part independent of each other. Hepatocyte death triggers compensatory proliferation of remnant hepatocytes in order to maintain liver homeostasis [2,3]. Liver injury stimulates the activation of resting, vitamin A-storing Hepatic Stellate Cells (HSCs) into proliferating, activated and ECM-producing myofibroblasts [4]. The latter ones are further characterized by expression of alpha smooth muscle actin (αSMA) and collagens in the liver [5]
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