Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro
Pharmacological Inhibition of Cyclin-Dependent Kinases Triggers Anti-Fibrotic Effects in Hepatic Stellate Cells In Vitro
复制标题
DOI：
10.3390/ijms21093267
复制
发表时间：
2020-05-01
影响因子：
5.6
通讯作者：
Liedtke, Christian
中科院分区：
文献类型：
--
作者：
Huebbers, Anna;Hennings, Julia;Liedtke, Christian
肝纤维化是慢性肝损伤后的伤口愈合过程，其特征是肝星状细胞（Hepatic Stellate Cells, hsc）产生的细胞外胶原蛋白积累。这一过程包括细胞周期再进入和正常休眠的造血干细胞的增殖，这些造血干细胞是由细胞周期蛋白和相关的细胞周期蛋白依赖性激酶（Cdks）控制的。Cdk2在e型和a型细胞周期蛋白复合物中介导s期的进入和进展。我们已经证明细胞周期蛋白E1对小鼠肝纤维化至关重要，但尚不清楚这是否依赖于Cdk2或相关Cdks。在这里，我们旨在评估泛cdk抑制剂CR8在体外治疗肝纤维化的益处。cr8处理降低了永生化HSC系的增殖和存活，此外还减弱了原代小鼠HSC的促纤维化特性。重要的是，原代小鼠肝细胞对CR8的细胞毒性和抗增殖作用具有更强的耐受性。我们确定了CR8剂量介导原代造血干细胞的抗纤维化作用，而不影响原代肝细胞的细胞周期活性和存活。综上所述，药理学泛cdk抑制剂CR8限制了造血干细胞的促纤维化特性，同时至少在体外保持了肝细胞的增殖和活力。因此，CR8及相关药物可能有利于肝纤维化的治疗。
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.