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Time-resolved hierarchical modeling highlights metabolites influencing productivity and cell death in Chinese hamster ovary cells
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0009-0009-7323-192X
Sartorius Corporate Research, Brussels, Belgium.
Umeå University, Faculty of Science and Technology, Department of Chemistry. Sartorius Corporate Research, Umeå, Sweden.ORCID iD: 0000-0003-3799-6094
Sartorius Stedim Biotech GmbH, Göttingen, Germany.
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2025 (English)In: Biotechnology Journal, ISSN 1860-6768, E-ISSN 1860-7314, Vol. 20, no 3, article id e202400624Article in journal (Refereed) Published
Abstract [en]

Biopharmaceuticals are medical compounds derived from biological sources and are often manufactured by living cells, primarily Chinese hamster ovary (CHO) cells. CHO cells display variation among cell clones, leading to growth and productivity differences that influence the product's quantity and quality. The biological and environmental factors behind these differences are not fully understood. To identify metabolites with a consistent relationship to productivity or cell death over time, we analyzed the extracellular metabolome of 11 CHO clones with different growth and productivity characteristics over 14 days. However, in bioreactor processes, metabolic profiles and process variables are both strongly time-dependent, confounding the metabolite-process variable relationship. To address this, we customized an existing hierarchical approach for handling time dependency to highlight metabolites with a consistent correlation to a process variable over a selected timeframe. We benchmarked this new method against conventional orthogonal partial least squares (OPLS) models. Our hierarchical method highlighted several metabolites consistently related to productivity or cell death that the conventional method missed. These metabolites were biologically relevant; most were known already, but some that had not been reported in CHO literature before, such as 3-methoxytyrosine and succinyladenosine, had ties to cell death in studies with other cell types. The metabolites showed an inverse relationship with the response variables: those positively correlated with productivity were typically negatively correlated with the death rate, or vice versa. For both productivity and cell death, the citrate cycle and adjacent pathways (pyruvate, glyoxylate, pantothenate) were among the most important. In summary, we have proposed a new method to analyze time-dependent omics data in bioprocess production. This approach allowed us to identify metabolites tied to cell death and productivity that were not detected with traditional models.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2025. Vol. 20, no 3, article id e202400624
Keywords [en]
bioprocess data, Chinese hamster ovary (CHO) cells, death rate, hierarchical modeling, metabolomics, orthogonal partial least squares (OPLS), productivity
National Category
Medical Biotechnology (Focus on Cell Biology, (incl. Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-237157DOI: 10.1002/biot.202400624ISI: 001441224200001PubMedID: 40065671Scopus ID: 2-s2.0-105000082543OAI: oai:DiVA.org:umu-237157DiVA, id: diva2:1952085
Available from: 2025-04-14 Created: 2025-04-14 Last updated: 2025-04-14Bibliographically approved

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Eriksson, AndreasTrygg, JohanAntti, HenrikJonsson, Pär
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