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A high-content, in vitro cardiac fibrosis assay for high-throughput, phenotypic identification of compounds with anti-fibrotic activity.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2020-04-08 , DOI: 10.1016/j.yjmcc.2020.04.002
G Palano 1 , M Jansson 2 , A Backmark 3 , S Martinsson 2 , A Sabirsh 4 , K Hultenby 5 , P Åkerblad 2 , K L Granberg 6 , K Jennbacken 2 , E Müllers 2 , E M Hansson 1
Affiliation  

A key feature in the pathogenesis of heart failure is cardiac fibrosis, but effective treatments that specifically target cardiac fibrosis are currently not available. A major impediment to progress has been the lack of reliable in vitro models with sufficient throughput to screen for activity against cardiac fibrosis. Here, we established cell culture conditions in micro-well format that support extracellular deposition of mature collagen from primary human cardiac fibroblasts - a hallmark of cardiac fibrosis. Based on robust biochemical characterization we developed a high-content phenotypic screening platform, that allows for high-throughput identification of compounds with activity against cardiac fibrosis. Our platform correctly identifies compounds acting on known cardiac fibrosis pathways. Moreover, it can detect anti-fibrotic activity for compounds acting on targets that have not previously been reported in in vitro cardiac fibrosis assays. Taken together, our experimental approach provides a powerful platform for high-throughput screening of anti-fibrotic compounds as well as discovery of novel targets to develop new therapeutic strategies for heart failure.

中文翻译:

一种高含量的体外心脏纤维化测定法,用于具有抗纤维化活性的化合物的高通量,表型鉴定。

心力衰竭的发病机制中的关键特征是心脏纤维化,但是目前尚没有针对心脏纤维化的有效治疗方法。取得进展的主要障碍是缺乏可靠的体外模型,该模型没有足够的通量来筛选针对心脏纤维化的活性。在这里,我们以微孔格式建立了细胞培养条件,以支持人原代心脏成纤维细胞中成熟胶原的细胞外沉积,这是心脏纤维化的标志。基于强大的生化特性,我们开发了一个高含量的表型筛选平台,可以高通量鉴定具有抗心脏纤维化活性的化合物。我们的平台可正确识别作用于已知心脏纤维化途径的化合物。此外,它可以检测作用于目标的化合物的抗纤维化活性,而该目标先前在体外心脏纤维化测定中尚未报道。总之,我们的实验方法为高通量筛选抗纤维化化合物以及发现新靶标提供了强大的平台,以开发新的心力衰竭治疗策略。
更新日期:2020-04-09
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