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Genome-scale modeling of CHO cells unravel the critical role of asparagine in cell culture feed media
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  • Kuin Tian Pang,
  • Yi Fan Hong,
  • Fumi Shozui,
  • Shunpei Furomitsu,
  • Matthew Myint,
  • Ying Swan Ho,
  • Yaron R. Silberberg,
  • Ian Walsh,
  • Meiyappan Lakshmanan
Kuin Tian Pang
Bioprocessing Technology Institute
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Yi Fan Hong
Bioprocessing Technology Institute
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Fumi Shozui
Ajinomoto Co Inc
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Shunpei Furomitsu
Ajinomoto Co Inc
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Matthew Myint
Bioprocessing Technology Institute
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Ying Swan Ho
Bioprocessing Research Industry Club
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Yaron R. Silberberg
Ajinomoto CELLiST Korea, Co., Inc,
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Ian Walsh
Bioprocessing Technology Institute
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Meiyappan Lakshmanan
Indian Institute of Technology Madras

Corresponding Author:[email protected]

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Abstract

Amino acids, including asparagine, aspartate, glutamine, and glutamate, play important roles in the purine and pyrimidine biosynthesis as well as serve as anaplerotic sources fueling the tricarboxylic acid (TCA) cycle for mitochondrial energy generation in mammalian cells. Despite extensive studies on glutamine and glutamate in CHO cell cultures, the roles of asparagine and aspartate, especially in feed media, remain underexplored. In this study, we utilized the CHO genome scale model to first deeply characterize the intracellular metabolic states of CHO cells cultured in different combinations of basal and feed media to understand the traits of asparagine/aspartate-dependent and glutamate-dependent feeds. Subsequently, we identified the critical role of asparagine and aspartate in the feed media as anaplerotic sources and conduct in silico simulations to ascertain their optimal ratios to improve cell culture performance. Finally, based on the model simulations, we reformulated the feed media by tailoring the concentrations of asparagine and aspartate. Our experimental data reveal a CHO cell preference for asparagine compared with aspartate, and thus maintaining an optimal ratio of these amino acids is a key factor for achieving optimal CHO cell culture performance in biopharmaceutical production.
04 Feb 2024Submitted to Biotechnology Journal
06 Feb 2024Review(s) Completed, Editorial Evaluation Pending
06 Feb 2024Submission Checks Completed
06 Feb 2024Assigned to Editor
07 Feb 2024Reviewer(s) Assigned
18 Apr 2024Editorial Decision: Revise Major
04 Aug 20241st Revision Received
02 Sep 2024Submission Checks Completed
02 Sep 2024Assigned to Editor
02 Sep 2024Review(s) Completed, Editorial Evaluation Pending
02 Sep 2024Reviewer(s) Assigned
16 Sep 2024Editorial Decision: Revise Minor
05 Oct 20242nd Revision Received
06 Oct 2024Submission Checks Completed
06 Oct 2024Assigned to Editor
06 Oct 2024Review(s) Completed, Editorial Evaluation Pending
07 Oct 2024Editorial Decision: Accept