Especially for the production of artificial, difficult to express molecules a further development of the CHO production cell line is required to keep pace with the continuously increasing demands. However, the identification of novel targets for cell line engineering to improve CHO cells is a time and cost intensive process. Since plasma cells are evolutionary optimized for a high antibody expression in mammals, we performed a comprehensive multi-omics comparison between CHO and plasma cells to exploit optimized cellular production traits. Comparing the transcriptome, proteome, miRNome, surfaceome and secretome of both cell lines identified key differences including 392 potential overexpression targets for CHO cell engineering categorized in 15 functional classes like transcription factors, protein processing or secretory pathway. In addition, 3 protein classes including 209 potential knock-down/out targets for CHO engineering were determined likely to affect aggregation or proteolysis. For production phenotype engineering, several of these novel targets were successfully applied to transient and transposase mediated overexpression or knock-down strategies to efficiently improve productivity of CHO cells. Thus, substantial improvement of CHO productivity was achieved by taking nature as a blueprint for cell line engineering.

中文翻译：

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自然为蓝图：基于与浆细胞的多组学比较的 CHO 生产细胞的全局表型工程


特别是对于难以表达的人工分子的生产，需要进一步开发 CHO 生产细胞系，以满足不断增长的需求。然而，确定细胞系工程的新靶标以改善 CHO 细胞是一个时间和成本密集的过程。由于浆细胞针对哺乳动物中的高抗体表达进行了进化优化，因此我们在 CHO 和浆细胞之间进行了全面的多组学比较，以利用优化的细胞生产特征。比较两种细胞系的转录组、蛋白质组、miRNome、表面组和分泌组，发现了关键差异，包括 CHO 细胞工程的 392 个潜在过表达靶点，分为 15 个功能类别，如转录因子、蛋白质加工或分泌途径。此外，还确定了 3 种蛋白质类别，包括 209 个 CHO 工程的潜在敲除/淘汰靶标，可能会影响聚集或蛋白水解。对于生产表型工程，其中一些新靶标已成功应用于瞬时和转座酶介导的过表达或敲低策略，以有效提高 CHO 细胞的生产力。因此，以自然为细胞系工程的蓝图，实现了 CHO 生产力的显着提高。