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Article

Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro

1
Department of Internal Medicine III, University Hospital, RWTH Aachen University, D-52074 Aachen, Germany
2
Department of Genetics, Physiology, and Microbiology, Faculty of Biology, Complutense University Madrid, 28040 Madrid, Spain
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(9), 3267; https://doi.org/10.3390/ijms21093267
Received: 24 April 2020 / Revised: 28 April 2020 / Accepted: 2 May 2020 / Published: 5 May 2020
(This article belongs to the Special Issue Pathophysiology of Liver Fibrosis and Its Therapies)
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. View Full-Text
Keywords: hepatic stellate cells; liver fibrosis; cyclin-dependent kinase; CR8; cell cycle; DNA repair hepatic stellate cells; liver fibrosis; cyclin-dependent kinase; CR8; cell cycle; DNA repair
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MDPI and ACS Style

Hübbers, A.; Hennings, J.; Lambertz, D.; Haas, U.; Trautwein, C.; Nevzorova, Y.A.; Sonntag, R.; Liedtke, C. Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro. Int. J. Mol. Sci. 2020, 21, 3267. https://doi.org/10.3390/ijms21093267

AMA Style

Hübbers A, Hennings J, Lambertz D, Haas U, Trautwein C, Nevzorova YA, Sonntag R, Liedtke C. Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro. International Journal of Molecular Sciences. 2020; 21(9):3267. https://doi.org/10.3390/ijms21093267

Chicago/Turabian Style

Hübbers, Anna, Julia Hennings, Daniela Lambertz, Ute Haas, Christian Trautwein, Yulia A. Nevzorova, Roland Sonntag, and Christian Liedtke. 2020. "Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro" International Journal of Molecular Sciences 21, no. 9: 3267. https://doi.org/10.3390/ijms21093267

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