Pharmacological inhibition of cyclin-dependent kinases triggers anti-fibrotic effects in hepatic stellate cells in vitro

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Hübbers, Anna and Hennings, Julia and Lambertz, Daniela and Haas, Ute and Trautwein, Christian and Nevzorova, Yulia A. and Sonntag, Roland and Liedtke, Christian (2020) Pharmacological inhibition of cyclin-dependent kinases triggers anti-fibrotic effects in hepatic stellate cells in vitro. International journal of molecular sciences, 21 (9). pp. 1-22. ISSN 1661-6596, ESSN 1422-0067

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Official URL: https://www.mdpi.com/1422-0067/21/9/3267



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.


Item Type:Article
Uncontrolled Keywords:Hepatic stellate cells; Liver fibrosis; Cyclin-dependent kinase; CR8; Cell cycle; DNA repair
Subjects:Medical sciences > Medicine > Gastroenterology and Hepatology
Medical sciences > Biology > Molecular biology
ID Code:62138
Deposited On:15 Sep 2020 11:09
Last Modified:18 Oct 2021 10:11

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