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Cited by 14Transgenic Plants and ApplicationsPlant tissue culture and regenerationViral Infectious Diseases and Gene Expression in Insects

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Process Engineering of Biopharmaceutical Production in Moss Bioreactors via Model-Based Description and Evaluation of Phytohormone Impact

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Ruiz-Molina, Natalia, Parsons, Juliana, Schroeder, Sina, Posten, Clemens, Reski, Ralf, Decker, Eva L.·2022·Frontiers in Bioengineering and Biotechnology
DOI 10.3389/fbioe.2022.837965PMC PMC8891706

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Abstract

The moss Physcomitrella is an interesting production host for recombinant biopharmaceuticals. Here we produced MFHR1, a synthetic complement regulator which has been proposed for the treatment of diseases associated to the complement system as part of human innate immunity. We studied the impact of different operation modes for the production process in 5 L stirred-tank photobioreactors. The total amount of recombinant protein was doubled by using fed-batch or batch compared to semi-continuous operation, although the maximum specific productivity (mg MFHR1/g FW) increased just by 35%. We proposed an unstructured kinetic model which fits accurately with the experimental data in batch and semi-continuous operation under autotrophic conditions with 2% CO 2 enrichment. The model is able to predict recombinant protein production, nitrate uptake and biomass growth, which is useful for process control and optimization. We investigated strategies to further increase MFHR1 production. While mixotrophic and heterotrophic conditions decreased the MFHR1-specific productivity compared to autotrophic conditions, addition of the phytohormone auxin (NAA, 10 µM) to the medium enhanced it by 470% in shaken flasks and up to 230% and 260%, in batch and fed-batch bioreactors, respectively. Supporting this finding, the auxin-synthesis inhibitor L-kynurenine (100 µM) decreased MFHR1 production significantly by 110% and 580% at day 7 and 18, respectively. Expression analysis revealed that the MFHR1 transgene, driven by the Physcomitrella actin5 ( PpAct5 ) promoter, was upregulated 16 h after NAA addition and remained enhanced over the whole process, whereas the auxin-responsive gene PpIAA1A was upregulated within the first 2 hours, indicating that the effect of auxin on PpAct5 promoter-driven expression is indirect. Furthermore, the day of NAA supplementation was crucial, leading to an up to 8-fold increase of MFHR1-specific productivity (0.82 mg MFHR1/g fresh weight, 150 mg accumulated over 7 days) compared to the productivity reported previously. Our findings are likely to be applicable to other plant-based expression systems to increase biopharmaceutical production and yields.

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    “89) (Maier et al., 2009; Schwanhäusser et al., 2011), a better correlation was reported for individual proteins which are essential for growth, such as those implied in energy metabolism (Nie et al.”
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Metadata

Authors
Ruiz-Molina, N., Parsons, J., Schroeder, S., Posten, C., Reski, R., & Decker, E. L.
Affiliations
  • University of Freiburg (DE)
  • Karlsruhe Institute of Technology (DE)
Corresponding author
Decker, Eva L.
ORCID
Venue
Frontiers in Bioengineering and Biotechnology
Publisher
Frontiers Media SA
Published
2022-02-17
Volume
10
Pages
837965-837965
ISSN
2296-4185 (ISSN-L)
DOI
10.3389/fbioe.2022.837965
PMC
PMC8891706
OpenAlex
W4225355831
Cited by
14
References
1
Citations by year
2026: 7 · 2025: 2 · 2024: 3 · 2023: 2
FWCI
0.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Bioengineering and Biotechnology (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • Repository KITopen (Karlsruhe Institute of Technology) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • KITopen (cc-by)
Funders
Deutsche Forschungsgemeinschaft (EXC-2189)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Transgenic Plants and Applications
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Plant tissue culture and regeneration
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Viral Infectious Diseases and Gene Expression in Insects
Keywords
Physcomitrella, recombinant protein expression, complement regulatory proteins, auxin, NAA, L-kynurenine, unstructured kinetic model, fed-batch operation, semi-continuous operation, nitrate uptake, plant-based expression systems, biopharmaceutical manufacturing

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