Abstract
More than a century has passed since the first attempt to cultivate plant cells in vitro. During this time, plant cell cultures have become increasingly attractive and cost-effective alternatives to classical approaches for the mass production of plant-derived metabolites. Furthermore, plant cell culture is the only economically feasible way of producing some high-value metabolites (e.g., paclitaxel) from rare and/or threatened plants. This review summarizes recent advances in bioprocessing aspects of plant cell cultures, from callus culture to product formation, with particular emphasis on the development of suitable bioreactor configurations (e.g., disposable reactors) for plant cell culture-based processes; the optimization of bioreactor culture environments as a powerful means to improve yields; bioreactor operational modes (fed-batch, continuous, and perfusion); and biomonitoring approaches. Recent trends in downstream processing are also considered.
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References
Anderlei T, Zang W, Papaspyrou M, Büchs J (2004) Online respiration activity measurement (OTR, CTR, RQ) in shake flasks. Biochem Eng J 17:187–194
Benavides J, Aguilar O, Lapizco-Encinas B, Rito-Palomares M (2008) Extraction and purification of bioproducts and nanoparticles using aqueous two-phase systems strategies. Chem Eng Technol 6:838–845
Bentebibel S, Moyano E, Palazon J, Cusido RM, Bonfill M, Eibl R, Pinol MT (2005) Effects of immobilization by entrapment in alginate and scale-up on paclitaxel and baccatin III production in cell suspension cultures of Taxus baccata. Biotechnol Bioeng 89:647–655
Büchs J (2001) Introduction to advantages and problems of shaken cultures. Biochem Eng J 7:91–98
Chakraborty A, Chattopadhyay S (2008) Stimulation of menthol production in Mentha piperita cell culture. In Vitro Cell Dev Biol Plant 44:518–524
Chilton MD (2001) Agrobacterium. A memoir. Plant Physiol 126:9–14
Chisti Y (1999a) Shear sensitivity. In: Flickinger MC, Drew SW (eds) Encyclopedia of bioprocess technology: fermentation, biocatalysis, and bioseparation, vol 5. Wiley, New York, pp 2379–2406
Chisti Y (1999b) Mass transfer. In: Flickinger MC, Drew SW (eds) Encyclopedia of bioprocess technology: fermentation, biocatalysis, and bioseparation, vol 3. Wiley, New York, pp 1607–1640
Cragg GM, Newman DJ (2009) Nature: a vital source of leads for anticancer drug development. Phytochem Rev 8:313–331
De Dobbeleer C, Cloutier M, Fouilland M, Legros R, Jolicoeur M (2006) A high-rate perfusion bioreactor for plant cells. Biotechnol Bioeng 95:1126–1137
De Luca V, St Pierre B (2000) The cell and developmental biology of alkaloids biosynthesis. Trends Plant Sci 5:168–173
Degerman M, Jakobsson N, Nilsson B (2008) Designing robust preparative purification processes with high performance. Chem Eng Technol 31:875–882
Doran PM (1999) Design of mixing systems for plant cell suspensions in stirred reactors. Biotechnol Prog 15:319–335
Ducos J-P, Terrier B, Courtois D (2009) Disposable bioreactors for plant micropropagation and mass plant cell culture. Adv Biochem Eng Biotechnol . doi:https://doi.org/10.1007/10_2008_8
Edahiro J, Yamada M, Seike S, Kakigi Y, Miyanaga K, Nakamura M, Seki M (2005) Separation of cultured strawberry cells producing anthocyanins in aqueous two-phase system. J Biosci Bioeng 100:449–454
Eibl R, Eibl D (2002) Bioreactors for plant cell and tissue cultures. In: Oksman-Caldentey K-M, Barz W (eds) Plant biotechnology and transgenic plants. Marcel Dekker, New York, pp 165–199
Eibl R, Eibl D (2006) Design and use of the wave bioreactor for plant cell culture. In: Gupta SD, Ibaraki Y (eds) Plant tissue culture engineering. Focus on biotechnology, vol 6. Springer, Dordrecht, pp 203–227
Eibl R, Eibl D (2008) Design of bioreactors suitable for plant cell and tissue culture. Phytochem Rev 7:593–598
Eibl R, Werner S, Eibl D (2009) Bag bioreactor based on wave-induced motion: characteristics and applications. Adv Biochem Eng Biotechnol . doi:https://doi.org/10.1007/10_2008_15
Georgiev M, Pavlov A, Ilieva M (2004) Rosmarinic acid production by Lavandula vera MM cell suspension: the effect of temperature. Biotechnol Lett 26:855–856
Georgiev M, Kuzeva S, Pavlov A, Kovacheva E, Ilieva M (2006a) Enhanced rosmarinic acid production by Lavandula vera MM cell suspension culture through elicitation with vanadyl sulfate. Z Naturforsch 61c:241–244
Georgiev M, Pavlov A, Ilieva M (2006b) Selection of high rosmarinic acid producing Lavandula vera MM cell lines. Process Biochem 41:2068–2071
Georgiev MI, Kuzeva SL, Pavlov AI, Kovacheva EG, Ilieva MP (2007a) Elicitation of rosmarinic acid by Lavandula vera MM cell suspension culture with abiotic elicitors. World J Microbiol Biotechnol 23:301–304
Georgiev M, Pavlov A, Bley T (2007b) Hairy root type plant in vitro systems as sources of bioactive substances. Appl Microbiol Biotechnol 74:1175–1185
Goossens A, Rischer H (2007) Implementation of functional genomics in alkaloid producing plants. Phytochem Rev 6:35–49
Ha S-J, Kim S-Y, Seo J-H, Oh D-K, Lee J-K (2007) Optimization of culture conditions and scale-up to pilot and plant scales for coenzyme Q10 production by Agrobacterium tumefaciens. Appl Microbiol Biotechnol 74:974–980
Haas C, Weber J, Ludwig-Mueller J, Deponte S, Bley T, Georgiev M (2008) Flow cytometry and phytochemical analysis of a sunflower cell suspension culture in a 5-L bioreactor. Z Naturforsch 63:699–705
Hanchinal VM, Survase SA, Sawant SK, Annapure US (2008) Response surface methodology in media optimization for production of β-carotene from Daucus carota. Plant Cell Tiss Organ Cult 93:123–132
Harada Y, Sakata K, Sato S, Takayama S (1997) Fermentation pilot plant. In: Vogel HC, Todaro CL (eds) Fermentation and biochemical engineering handbook. Principles, process design and equipment, 2nd edn. Noyes Publications, Westwood, New Jersey, USA, pp 1–66
Hartonen K, Parshntsev J, Sandberg K, Bergelin E, Nisula L, Riekkola M-L (2007) Isolation of flavonoids from aspen knotwood by pressurized hot water extraction and comparison with other extraction techniques. Talanta 74:32–38
Hostettmann K, Marston A, Hostettmann M (1998) Preparative chromatography techniques—applications in natural products isolation, 2nd edn. Springer, Berlin
Hu W-W, Yao H, Zhong JJ (2001) Improvement of Panax notoginseng cell culture for production of ginseng saponins and polysaccharide by high density cultivation in pneumatically agitated bioreactors. Biotechnol Prog 17:838–846
Huang T-K, McDonald KA (2009) Bioreactor engineering for recombinant protein production in plant cell suspension cultures. Biochem Eng J . doi:https://doi.org/10.1016/j.bej.2009.02.008
Huang M, Xu Y, Lv Q, Ren Q (2008) Separation and purification of β-carotene from chlorophyll factory residues. Chem Eng Technol 31:922–927
Iizuka Y, Kato R, Shibasaki-Kitakawa N, Yonemoto T (2005) Combination of extractive solvent addition and immobilization culture for continuous production of scopoletin by tobacco cells. Biotechnol Prog 21:603–607
Ito Y (2005) Golden rules and pitfalls in selecting optimum conditions for high-speed counter-current chromatography. J Chromatogr A 1065:145–168
James E, Lee JM (2000) An improved optical technique for monitoring plant cell concentration. Plant Cell Rep 19:283–285
Kang CD, Sim SJ (2007) Selective extraction of free astaxanthin from Haematococcus culture using a tandem organic solvent system. Biotechnol Prog 23:866–871
Kang CD, Sim SJ (2008) Direct extraction of free astaxanthin from Haematococcus culture using vegetable oils. Biotechnol Lett 30:441–444
Kieran P (2001) Bioreactor design for plant cell suspension cultures. In: Cabral JMS (ed) Principles of multiphase reactor design. Harwood Academic Publishers, New Jersey, pp 391–426
Kiselev KV, Dubrovina AS, Veselova MV, Bulgakova VP, Fedoreyev SA, Zhuravlev YN (2007) The rolB gene-induced overproduction of resveratrol in Vitis amurensis transformed cells. J Biotechnol 128:681–692
Kolewe ME, Gaurav V, Roberts SC (2008) Pharmaceutically active natural product synthesis and supply via plant cell culture technology. Mol Pharm 5:243–256
Kurosumi A, Kobayashi F, Mtui G, Nakamura Y (2006) Development of optimal culture method of Sparassis crispa and a new extraction method of antineoplastic constituent. Biochem Eng J 30:109–113
Linsmayer EM, Skoog F (1965) Organic growth factor requirements of tobacco tissue cultures. Physiol Plant 18:100–127
Luo J, Mei XG, Hu DW (2002) Improved paclitaxel production by fed-batch suspension cultures of Taxus chinensis in bioreactors. Biotechnol Lett 24:561–565
Maciuk A, Georgiev MI, Toribio A, Zèches-Hanrot M, Ilieva MP, Nuzillard JM, Renault JH (2005) Purification of rosmarinic acid by strong ion-exchange centrifugal partition chromatography. J Liq Chromatogr Relat Technol 28:1947–1957
Maltese F, van der Kooy F, Verpoorte R (2009) Solvent derived artifacts in natural products chemistry. Nat Prod Commun 4:447–454
Mandal V, Mohan Y, Hemalatha S (2007) Microwave assisted extraction—an innovative and promising extraction tool for medicinal plant research. Phcog Rev 1:7–18
Matkowski A (2008) Plant in vitro culture for the production of antioxidants—a review. Biotechnol Adv 26:548–560
Murashige T, Skoog F (1962) A revised medium for rapid growth and bioassays with tobacco tissue cultures. Physiol Plant 15:473–497
Newman DJ, Cragg GM, Snader KM (2003) Natural products as sources of new drugs over the period 1981–2002. J Nat Prod 66:1022–1037
Oksman-Caldentey K-M, Inze D (2004) Plant cell factories in the post-genomic era: new ways to produce designer secondary metabolites. Trends Plant Sci 9:433–440
Pauli GF, Pro SM, Friesen JB (2008) Countercurrent separation of natural products. J Nat Prod 71:1489–1508
Pavlov A, Panchev I, Ilieva M (2000) Nutrient medium optimization for rosmarinic acid production by Lavandula vera MM cell suspension. Biotechnol Prog 16:688–670
Pavlov A, Georgiev M, Ilieva M (2005a) Production of rosmarinic acid by Lavandula vera MM cell suspension in bioreactor: effect of dissolved oxygen concentration and agitation. World J Microbiol Biotechnol 21:389–392
Pavlov A, Georgiev M, Panchev I, Ilieva M (2005b) Optimization of rosmarinic acid production by Lavandula vera MM plant cell suspension in a laboratory bioreactor. Biotechnol Prog 21:394–396
Pavlov A, Popov S, Kovacheva E, Georgiev M, Ilieva M (2005c) Volatile and polar compounds in Rosa damascena Mill 1803 cell suspension. J Biotechnol 118:89–97
Powell EE, Hill GA, Juurlink BHJ, Carrier DJ (2005a) Glucoraphanin extraction from Cardaria draba: part 1. Optimization of batch extraction. J Chem Technol Biotechnol 80:985–991
Powell EE, Hill GA, Juurlink BHJ, Carrier DJ (2005b) Glucoraphanin extraction from Cardaria draba: part 2. Countercurrent extraction, bioactivity and toxicity testing. J Chem Technol Biotechnol 80:992–997
Prakash G, Srivastava AK (2007) Azadirachtin production in stirred tank reactors by Azadirachta indica suspension culture. Process Biochem 42:93–97
Prakash G, Srivastava AK (2008) Statistical elicitor optimization studies for the enhancement of azadirachtin production in bioreactor Azadirachta indica cell cultivation. Biochem Eng J 40:218–226
Qian Z-G, Zhao Z-J, Xu Y, Qian X, Zhong JJ (2006) Novel synthetic 2,6-dichloroisonicotinate derivates as effective elicitors for inducing the biosynthesis of plant secondary metabolites. Appl Mircobiol Biotechnol 71:164–167
Raval KN, Hellwig S, Prakash G, Ramos-Plasencia A, Srivastava A, Büchs J (2003) Necessity of a two-stage process for the production of azadirachtin-related limonoids in suspension cultures of Azadirachta indica. J Biosci Bioeng 96:16–22
Renault JH, Nuzillard JM, Intes O, Maciuk A (2002) Countercurrent chromatography—the support-free liquid stationary phase in countercurrent chromatography. In: Barcelo D (ed) Wilson & Wilson’s comprehensive analytical chemistry, vol 38. Elsevier Science BV, Amsterdam, pp 49–83
Reverchon E, de Marco I (2006) Supercritical fluid extraction and fractionation of natural matter. J Supercrit Fluids 38:146–166
Rischer H, Oresic M, Seppanen-Laakso T, Katajamaa M, Lammertyn F, Ardiles-Diaz W, Van Montagu MCE, Inze D, Oksman-Caldentey K-M, Goossens A (2006) Gene-to-metabolite networks for terpenoid indole alkaloid biosynthesis in Catharanthus roseus cells. Proc Natl Acad Sci U S A 103:5614–5619
Ritterhaus E, Ulrich J, Westphal K (1990) Large-scale production of plant cell cultures. IAPTC Newsl 61:2–10
Romanik G, Gilgenast E, Przyjazny A, Kaminski M (2007) Techniques of preparing plant material for chromatographic separation and analysis. J Biochem Biophys Methods 70:253–261
Routien JB, Nickell LG (1956) Cultivation of plant tissue. US Patent 2(747):334
Samorski M, Muller-Newen G, Büchs J (2005) Quasi-continuous combined scattered light and fluorescence measurements: a novel measurement technique for shaken microtiter plates. Biotechnol Bioeng 92:61–68
Sarker SD, Latif Z, Gray AI (2005) Methods in biotechnologies, series 20: natural products isolation, 2nd edn. Humana Press, Totowa, NJ
Schmidt-Traub H (2005) Preparative chromatography of fine chemicals and pharmaceutical agents. Wiley-VCH, Weinheim
Silveira ST, Quines LKDM, Burkert CAV, Kalil SJ (2008) Separation of phycocyanins from Spirulina platensis using ion exchange chromatography. Bioproc Biosyst Eng 31:477–482
Singh NK, Parmar A, Madamwar D (2009) Optimization of medium components for increased production of phycocyanin from Phormidium ceylanicum and its purification by single step process. Bioresour Technol 100:1663–1669
Smetanska I (2008) Production of secondary metabolites using plant cell cultures. Adv Biochem Eng Biotechnol 111:187–228
Su WW, Arias R (2003) Continuous plant cell perfusion culture: bioreactor characterization and secreted enzyme production. J Biosci Bioeng 95:13–20
Ten Hoopen HJG, Vinke JL, Moreno PRH, Verpoorte R, Heijnen JJ (2002) Influence of temperature on growth and ajmalicine production by Catharanthus roseus suspension cultures. Enzyme Microb Technol 30:56–65
Terrier B, Courtois D, Henault N, Cuvier A, Bastin M, Aknin A, Dubreuil J, Petiard V (2007) Two new disposable bioreactors for plant cell culture: the wave and undertow bioreactor and the slug bubble bioreactor. Biotechnol Bioeng 96:914–923
Toribio A, Delannay E, Richard B, Ple K, Zeches-hanrot M, Nuzillard JM, Renault JH (2007a) Preparative isolation of huperzine A and B from Huperzia serrata by displacement centrifugal partition chromatography. J Chromatogr A 1140:101–106
Toribio A, Nuzillard JM, Renault JH (2007b) Strong ion-exchange centrifugal partition chromatography as an efficient method for the large-scale purification of glucosinolates. J Chromatogr A 1170:44–51
Van Gulik WM, Ten Hoopen HJG, Heijnen JJ (1992) Kinetics and stoichiometry of growth of plant cell cultures of Catharanthus roseus and Nicotiana tabacum in batch and continuous fermentors. Biotechnol Bioeng 40:863–874
Van Gulik WM, Ten Hoopen HJG, Heijnen JJ (1993) A structured model describing carbon and phosphate limited growth of Catharanthus roseus plant cell suspension in batch and chemostat culture. Biotechnol Bioeng 41:771–780
Van Gulik WM, Ten Hoopen HJG, Heijnen JJ (2001) The application of continuous culture for plant cell suspension. Enzyme Microb Technol 28:796–805
Vasil IK (2008) A history of plant biotechnology: from the cell theory of Schleiden and Schwann to biotech crops. Plant Cell Rep 27:1423–1440
Verpoorte R, Contin A, Memelink J (2002) Biotechnology for the production of plant secondary metabolites. Phytochem Rev 1:13–25
Wang SJ, Zhong JJ (1996) A novel centrifugal impeller bioreactor. I. Fluid circulation, mixing, and liquid velocity profiles. Biotechnol Bioeng 51:511–519
Wang W, Zhao Z-J, Xu Y, Qian X, Zhong JJ (2006) Efficient induction of ginsenoside biosynthesis and alteration of ginsenoside heterogeneity in cell cultures of Panax. Appl Microbiol Biotechnol 70:298–307
Xie JJ, Lu J, Qian ZM, Yu Y, Duan JA, Li SP (2009) Optimization and comparison of five methods for extraction of coniferyl ferulate from Angelica sinensis. Molecules 14:555–565
Xu Y, Zhao Z, Qian X, Qian Z, Tian W, Zhong JJ (2006) Novel, unnatural benzo-1,2,3-thiadiazole-7-carboxylate elicitors of taxoid biosynthesis. J Agric Food Chem 54:8793–8798
Yanpaisan W, King NJC, Doran PM (1999) Flow cytometry of plant cells with applications in large-scale bioprocessing. Biotechnol Adv 17:3–27
Zhang Z-Y, Zhong JJ (2004) Scale-up of centrifugal impeller bioreactor for hyperproduction of ginseng saponins and polysaccharide by high-density cultivation of Panax notoginseng cells. Biotechnol Prog 20:1076–1081
Zhao D, Xing J, Li M, Lu D, Zhao Q (2001) Optimization of growth and jaceosidin production in callus and cell suspension cultures of Saussurea medusa. Plant Cell Tissue Organ Cult 67:227–234
Zhao J, Davis LC, Verpoorte R (2005) Elicitor signal transduction leading to production of plant secondary metabolites. Biotechnol Adv 23:283–333
Zhong JJ, Fujiyama K, Seki T, Yoshida T (1993) On-line monitoring of cell concentration of Perilla frutescens in a bioreactor. Biotechnol Bioeng 42:542–546
Zhong JJ, Fujiyama K, Seki T, Yoshida T (1994a) A quantitative analysis of shear effects on cell suspension and cell culture of Perilla frutescens in bioreactors. Biotechnol Bioeng 44:649–654
Zhong JJ, Konstantinov KB, Yoshida T (1994b) Computer-aided on-line monitoring of physiological variables of cell cultures of Perilla frutescens in a bioreactor. J Ferment Bioeng 77:445–447
Acknowledgements
We thank Dr. V. Georgiev for preparing Fig. 1, and Profs. J.J. Zhong (Shanghai Jiao Tong University), Y. Xu, and X. Qian (East China University of Science and Technology, Shanghai, China) for providing us with the relative prices of the novel elicitors synthesized and used in their laboratories. Special thanks goes to D. Ullisch, R. Huber, and Prof. Dr. J. Büchs (chair of Biochemical Engineering, Aachen University of Technology, Germany) for providing us with the MTP cultivations data. This work has been supported by a National Science Fund of Bulgaria under contract number DO 02-261/2008.
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This paper is dedicated to Prof. Dr. Mladenka P. Ilieva on the occasion of her 70th birthday.
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Georgiev, M.I., Weber, J. & Maciuk, A. Bioprocessing of plant cell cultures for mass production of targeted compounds. Appl Microbiol Biotechnol 83, 809–823 (2009). https://doi.org/10.1007/s00253-009-2049-x
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DOI: https://doi.org/10.1007/s00253-009-2049-x