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

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

Dynamic culture of human liver equivalents inside a micro-bioreactor for long-term substance testing : From 23rd European Society for Animal Cell Technology (ESACT) Meeting: Better Cells for Better Health Lille, France. 23-26 June 2013

Published by BioMed Central: Materne, Eva-Maria et al.: Dynamic culture of human liver equivalents inside a micro-bioreactor for longterm substance testing. - In: BMC Proceedings. - ISSN 1753-6561 (online). - 7 (2012), suppl. 6, art. P72. - doi:10.1186/1753-6561-7-S6-P72

A dynamic multi-organ-chip for long-term cultivation and substance testing proven by 3D human liver and skin tissue co-culture

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Current in vitro and animal tests for drug development are failing to emulate the systemic organ complexity of the human body and, therefore, to accurately predict drug toxicity. In this study, we present a multi-organ-chip capable of maintaining 3D tissues derived from cell lines, primary cells and biopsies of various human organs. We designed a multi-organ-chip with co-cultures of human artificial liver microtissues and skin biopsies, each a 1/100 000 of the biomass of their original human organ counterparts, and have successfully proven its long-term performance. The system supports two different culture modes: i) tissue exposed to the fluid flow, or ii) tissue shielded from the underlying fluid flow by standard Transwell® cultures. Crosstalk between the two tissues was observed in 14-day co-cultures exposed to fluid flow. Applying the same culture mode, liver microtissues showed sensitivity at different molecular levels to the toxic substance troglitazone during a 6-day exposure. Finally, an astonishingly stable long-term performance of the Transwell®-based co-cultures could be observed over a 28-day period. This mode facilitates exposure of skin at the air–liquid interface. Thus, we provide here a potential new tool for systemic substance testing.BMBF, 0315569, GO-Bio 3: Multi-Organ-Bioreaktoren für die prädiktive Substanztestung im Chipforma

Gesundheitsfördernde Hochschulen: Konzepte, Strategien und Praxisbeispiele

Sonntag U, Gräser S, Stock C, Krämer A, eds. Gesundheitsfördernde Hochschulen: Konzepte, Strategien und Praxisbeispiele. Gesundheitsforschung. Weinheim: Juventa-Verl.; 2000

Gesundheitsförderung im Setting Hochschule. Wissenschaftliche Instrumente, Praxisbeispiele und Perspektiven

Krämer A, Sonntag U, Steinke B, Meier S, Hildbrand C, eds. Gesundheitsförderung im Setting Hochschule. Wissenschaftliche Instrumente, Praxisbeispiele und Perspektiven. Weinheim: Juventa-Verl.; 2007

Psychosoziale Belastung und psychosomatische Beschwerden von Studierenden. Ergebnisse einer Längsschnittstudie

Stock C, Krämer A. Psychosoziale Belastung und psychosomatische Beschwerden von Studierenden. Ergebnisse einer Längsschnittstudie. In: Sonntag U, Gräser S, Stock C, Krämer A, eds. Gesundheitsfördernde Hochschulen : Konzepte, Strategien und Praxisbeispiele. Gesundheitsforschung. Weinheim: Juventa-Verl.; 2000: 127-138