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Multi-omic characterization of antibody-producing CHO cell lines elucidates metabolic reprogramming and nutrient uptake bottlenecks.

Multi-omic characterization of antibody-producing CHO cell lines elucidates metabolic reprogramming and nutrient uptake bottlenecks.

Authors :
Gopalakrishnan, Saratram
Johnson, William
Valderrama-Gomez, Miguel A.
Icten, Elcin
Tat, Jasmine
Lay, Fides
Diep, Jonathan
Gomez, Natalia
Stevens, Jennitte
Schlegel, Fabrice
Rolandi, Pablo
Kontoravdi, Cleo
Lewis, Nathan E.
Source :
Metabolic Engineering. Sep2024, Vol. 85, p94-104. 11p.
Publication Year :
2024

Abstract

Characterizing the phenotypic diversity and metabolic capabilities of industrially relevant manufacturing cell lines is critical to bioprocess optimization and cell line development. Metabolic capabilities of production hosts limit nutrient and resource channeling into desired cellular processes and can have a profound impact on productivity. These limitations cannot be directly inferred from measured data such as spent media concentrations or transcriptomics. Here, we present an integrated multi-omic analysis pipeline combining exo-metabolomics, transcriptomics, and genome-scale metabolic network analysis and apply it to three antibody-producing Chinese Hamster Ovary cell lines to identify reprogramming features associated with high-producing clones and metabolic bottlenecks limiting product formation in an industrial bioprocess. Analysis of individual datatypes revealed a decreased nitrogenous byproduct secretion in high-producing clones and the topological changes in peripheral metabolic pathway expression associated with phase shifts. An integrated omics analysis in the context of the genome-scale metabolic model elucidated the differences in central metabolism and identified amino acid utilization bottlenecks limiting cell growth and antibody production that were not evident from exo-metabolomics or transcriptomics alone. Thus, we demonstrate the utility of a multi-omics characterization in providing an in-depth understanding of cellular metabolism, which is critical to efforts in cell engineering and bioprocess optimization. • Multi-omics analysis permits synergistic evaluation of culture performance. • Overall phenotypic changes were traced back to phase-specific metabolic reprogramming. • Reprogramming nitrogen usage and metabolism was associated with increased productivity. • Amino acid usage and channeling towards desired products limited productivity. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
10967176
Volume :
85
Database :
Academic Search Index
Journal :
Metabolic Engineering
Publication Type :
Academic Journal
Accession number :
179633697
Full Text :
https://doi.org/10.1016/j.ymben.2024.07.009