RT Journal Article
T1 Pharmacological inhibition of cyclin-dependent kinases triggers anti-fibrotic effects in hepatic stellate cells in vitro
A1 Hübbers, Anna
A1 Hennings, Julia
A1 Lambertz, Daniela
A1 Haas, Ute
A1 Trautwein, Christian
A1 Nevzorova, Yulia
A1 Sonntag, Roland
A1 Liedtke, Christian
AB 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.
PB MDPI
SN 1661-6596, ESSN 1422-0067
YR 2020
FD 2020-05-05
LK https://hdl.handle.net/20.500.14352/6536
UL https://hdl.handle.net/20.500.14352/6536
LA eng
NO Ministerio de Economía y Competitividad (MINECO)
NO Comunidad de Madrid
NO Ramón y Cajal Fellowship
NO German Research Foundation (DFG)
NO Interdisciplinary Center for Clinical Research (IZKF)
DS Docta Complutense
RD 12 abr 2025