期刊
BIOTECHNOLOGY AND BIOENGINEERING
卷 109, 期 6, 页码 1415-1429出版社
WILEY
DOI: 10.1002/bit.24445
关键词
mammalian systems biotechnology; CHO cells; constraints-based flux analysis; metabolomics; genome-scale metabolic model
资金
- Biomedical Research Council of A*STAR (Agency for Science, Technology and Research), Singapore
- Rural Development Administration, Republic of Korea [PJ008184]
- Agency for Science, Technology and Research, Singapore
- Next-Generation BioGreen 21 Program [PJ008184]
The increasing demand for recombinant therapeutic proteins highlights the need to constantly improve the efficiency and yield of these biopharmaceutical products from mammalian cells, which is fully achievable only through proper understanding of cellular functioning. Towards this end, the current study exploited a combined metabolomics and in silico modeling approach to gain a deeper insight into the cellular mechanisms of Chinese hamster ovary (CHO) fed-batch cultures. Initially, extracellular and intracellular metabolite profiling analysis shortlisted key metabolites associated with cell growth limitation within the energy, glutathione, and glycerophospholipid pathways that have distinct changes at the exponential-stationary transition phase of the cultures. In addition, biomass compositional analysis newly revealed different amino acid content in the CHO cells from other mammalian cells, indicating the significance of accurate protein composition data in metabolite balancing across required nutrient assimilation, metabolic utilization, and cell growth. Subsequent in silico modeling of CHO cells characterized internal metabolic behaviors attaining physiological changes during growth and non-growth phases, thereby allowing us to explore relevant pathways to growth limitation and identify major growth-limiting factors including the oxidative stress and depletion of lipid metabolites. Such key information on growth-related mechanisms derived from the current approach can potentially guide the development of new strategies to enhance CHO culture performance. Biotechnol. Bioeng. 2012; 109:14151429. (c) 2012 Wiley Periodicals, Inc.
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