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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以自然为蓝图：基于与浆细胞的多组学比较的 CHO 生产细胞的全球表型工程


特别是对于人工、难以表达的分子的生产，需要进一步开发 CHO 生产细胞系，以跟上不断增长的需求。然而，为细胞系工程确定新的靶点以改进 CHO 细胞是一个时间和成本密集型过程。由于浆细胞经过进化优化，可在哺乳动物中实现高抗体表达，因此我们对 CHO 和浆细胞进行了全面的多组学比较，以利用优化的细胞生产特性。比较两种细胞系的转录组、蛋白质组、miRNome、表面组和分泌组确定了关键差异，包括 392 个用于 CHO 细胞工程的潜在过表达靶标，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，确定了 3 种蛋白质类别，包括 209 个用于 CHO 工程的潜在敲低/输出靶标，可能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 细胞的生产率。因此，通过将自然作为细胞系工程的蓝图，实现了 CHO 生产率的实质性提高。