Barley grains for the production of endotoxin-free growth factors.

The most popular hosts for recombinant protein production have now in many cases passed their low-hanging-fruit era and their limitations as production hosts are becoming more evident. Therefore, the bioprocessing community is constantly on the lookout for new hosts that can complement the current selection. The development of plant systems is eagerly followed because of the great potential they show, such as much reduced production cost and absence of endotoxins and human pathogens. In this review, we describe the unique barley-based platform for recombinant protein production. We summarize the methods used for gene modification and protein processing and discuss the main advantages of the system. Finally, we discuss the significance of endotoxin-free proteins for cell-based research and therapeutic applications.

[1]  M. Szwacka,et al.  Genetically Modified Crops Expressing 35S-Thaumatin II Transgene: Sensory Properties and Food Safety Aspects , 2012 .

[2]  Rainer Fischer,et al.  Plant cell cultures for the production of recombinant proteins , 2004, Nature Biotechnology.

[3]  J. Kumlehn,et al.  phiC31 Integrase-Mediated Site-Specific Recombination in Barley , 2012, PloS one.

[4]  K. Deb,et al.  Endotoxin-induced silencing of mesoderm induction and functional differentiation: role of HMGB1 in pluripotency and infection. , 2008, Regenerative medicine.

[5]  Meijing Wang,et al.  Human mesenchymal stem cells stimulated by TNF-alpha, LPS, or hypoxia produce growth factors by an NF kappa B- but not JNK-dependent mechanism. , 2008, American journal of physiology. Cell physiology.

[6]  H. Liu,et al.  Evaluation of seed storage-protein gene 5′ untranslated regions in enhancing gene expression in transgenic rice seed , 2010, Theoretical and Applied Genetics.

[7]  Taiji Kawakatsu,et al.  Cereal seed storage protein synthesis: fundamental processes for recombinant protein production in cereal grains. , 2010, Plant biotechnology journal.

[8]  K. Kosová,et al.  Expression of dehydrins in wheat and barley under different temperatures. , 2011, Plant science : an international journal of experimental plant biology.

[9]  Jianfeng Xu,et al.  Green factory: plants as bioproduction platforms for recombinant proteins. , 2012, Biotechnology advances.

[10]  Y. Bae,et al.  Role of Toll‐Like Receptors on Human Adipose‐Derived Stromal Cells , 2006, Stem cells.

[11]  B. Svensson,et al.  Barley seed proteomics from spots to structures. , 2009, Journal of proteomics.

[12]  H. Giese,et al.  Synthesis of the major storage protein, hordein, in barley , 2004, Planta.

[13]  T. Stefánsson,et al.  Measuring gene flow in barley fields under Icelandic sub-arctic conditions using closed-flowering varieties , 2010 .

[14]  L. Fillaudeau,et al.  Investigation of Mechanisms Governing Membrane Fouling and Protein Rejection in the Sterile Microfiltration of Beer with an Organic Membrane , 1999 .

[15]  N. Callewaert,et al.  Production of Plant Made Pharmaceuticals: From Plant Host to Functional Protein , 2012 .

[16]  P. Waterhouse,et al.  Biopharming the SimpliRED™ HIV diagnostic reagent in barley, potato and tobacco , 2002, Molecular Breeding.

[17]  I. Díaz,et al.  The GAMYB protein from barley interacts with the DOF transcription factor BPBF and activates endosperm-specific genes during seed development. , 2002, The Plant journal : for cell and molecular biology.

[18]  P. Petersen,et al.  Endotoxins-the invisible companion in biomaterials research. , 2013, Tissue engineering. Part B, Reviews.

[19]  U. Hellman,et al.  Barley as a green factory for the production of functional Flt3 ligand , 2010, Biotechnology journal.

[20]  E. Vincze,et al.  Molecular analysis of transgene and vector backbone integration into the barley genome following Agrobacterium-mediated transformation , 2006, Plant Cell Reports.

[21]  M. Caroff,et al.  Structure of bacterial lipopolysaccharides. , 2003, Carbohydrate research.

[22]  K. Terpe.  Overview of bacterial expression systems for heterologous protein production: from molecular and biochemical fundamentals to commercial systems , 2006, Applied Microbiology and Biotechnology.

[23]  A. Karsan,et al.  Lipopolysaccharide Mediates Endothelial Apoptosis by a FADD-dependent Pathway* , 1998, The Journal of Biological Chemistry.

[24]  K. Müntz.  Deposition of storage proteins , 1998 .

[25]  Yun Kang,et al.  Endotoxin removal from protein solutions by immobilized metal ion affinity chromatography , 2000 .

[26]  T. Mckenna,et al.  Prolonged exposure of rat aorta to low levels of endotoxin in vitro results in impaired contractility. Association with vascular cytokine release. , 1990, The Journal of clinical investigation.

[27]  G. Hensel,et al.  Immature pollen-derived doubled haploid formation in barley cv. Golden Promise as a tool for transgene recombination , 2005, Acta Physiologiae Plantarum.

[28]  R. Stewart,et al.  Effects of β‐Glucans and Environmental Factors on the Viscosities of Wort and Beer , 2004 .

[29]  S. Streatfield,et al.  Approaches to achieve high-level heterologous protein production in plants. , 2007, Plant biotechnology journal.

[30]  Taiji Kawakatsu,et al.  The 3′-untranslated region of rice glutelin GluB-1 affects accumulation of heterologous protein in transgenic rice , 2009, Biotechnology Letters.

[31]  R. Flavell,et al.  Safe and acceptable strategies for producing foreign molecules in plants. , 2004, Current opinion in plant biology.

[32]  D. Douchkov,et al.  Transgene expression systems in the Triticeae cereals. , 2011, Journal of plant physiology.

[33]  T. Okazaki,et al.  Toll-like receptors (TLR) 2 and 4 on human sperm recognize bacterial endotoxins and mediate apoptosis. , 2011, Human reproduction.

[34]  Jianwei Zhu,et al.  Mammalian cell protein expression for biopharmaceutical production. , 2012, Biotechnology advances.

[35]  C. Ricordi,et al.  ENDOTOXIN-MEDIATED DELAYED ISLET GRAFT FUNCTION IS ASSOCIATED WITH INCREASED INTRA-ISLET CYTOKINE PRODUCTION AND ISLET CELL APOPTOSIS1 , 2001, Transplantation.

[36]  J. Austyn,et al.  Bacterial lipopolysaccharide contamination of commercial collagen preparations may mediate dendritic cell maturation in culture. , 1998, Journal of immunological methods.

[37]  J. Kumlehn,et al.  Agrobacterium-Mediated Gene Transfer to Cereal Crop Plants: Current Protocols for Barley, Wheat, Triticale, and Maize , 2009, International journal of plant genomics.

[38]  D. von Wettstein,et al.  T-DNA integration into the barley genome from single and double cassette vectors , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[39]  L. Wilken,et al.  Recovery and purification of plant-made recombinant proteins. , 2012, Biotechnology advances.

[40]  I. Chibata,et al.  Purification of High Molecular Weight Urokinase from Human Urine and Comparative Study of Two Active Forms of Urokinase , 1983, Thrombosis and Haemostasis.

[41]  D. Becker,et al.  Genetic transformation of barley (Hordeum vulgare L.) via infection of androgenetic pollen cultures with Agrobacterium tumefaciens. , 2006, Plant biotechnology journal.

[42]  G Gstraunthaler,et al.  Optimization of chemically defined cell culture media--replacing fetal bovine serum in mammalian in vitro methods. , 2010, Toxicology in vitro : an international journal published in association with BIBRA.

[43]  W. Harwood.  Advances and remaining challenges in the transformation of barley and wheat. , 2012, Journal of experimental botany.

[44]  Michael V Sefton,et al.  Endotoxin: the uninvited guest. , 2005, Biomaterials.

[45]  H. Vaikousi,et al.  Solution flow behavior and gelling properties of water-soluble barley (1→3,1→4)-β-glucans varying in molecular size , 2004 .

[46]  Mette Lange,et al.  Transformation of barley (Hordeum vulgare L.) by Agrobacterium tumefaciens infection of in vitro cultured ovules. , 2012, Methods in molecular biology.

[47]  M. Heydari,et al.  Optimization of Chemically Defined Cell Culture Media for Recombinant ONTAK Immunotoxin Production , 2014 .

[48]  W. Seeger,et al.  Endotoxin induces proliferation of NSCLC in vitro and in vivo: role of COX-2 and EGFR activation , 2012, Cancer Immunology, Immunotherapy.

[49]  Akhilesh K Tyagi,et al.  Advances in cereal genomics and applications in crop breeding. , 2006, Trends in biotechnology.

[50]  B. Lindner,et al.  Aggregates Are the Biologically Active Units of Endotoxin* , 2004, Journal of Biological Chemistry.

[51]  R. Twyman,et al.  Plant-derived pharmaceuticals--the road forward. , 2005, Trends in plant science.

[52]  M. Sakata,et al.  Chromatographic removal of endotoxin from protein solutions by polymer particles. , 2002, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[53]  Rainer Fischer,et al.  Molecular farming in plants: host systems and expression technology. , 2003, Trends in biotechnology.

[54]  T. Komatsuda,et al.  Cleistogamous flowering in barley arises from the suppression of microRNA-guided HvAP2 mRNA cleavage , 2009, Proceedings of the National Academy of Sciences.

[55]  C. Ricordi,et al.  Endotoxin Deactivation by Transient Acidification , 2010, Cell transplantation.

[56]  J. Kumlehn,et al.  Transgenic Barley in Fundamental Research and Biotechnology , 2007 .

[57]  V. Goldberg,et al.  Adherent endotoxin mediates biological responses of titanium particles without stimulating their phagocytosis , 2002, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[58]  V. Goldberg,et al.  Adherent Endotoxin on Orthopedic Wear Particles Stimulates Cytokine Production and Osteoclast Differentiation , 2001, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[59]  J. Snape,et al.  High-throughput Agrobacterium-mediated barley transformation , 2008, Plant Methods.

[60]  G. Sukhikh,et al.  Mesenchymal Stem Cells , 2002, Bulletin of Experimental Biology and Medicine.

[61]  Y. Haishima,et al.  Endotoxin contamination in wound dressings made of natural biomaterials. , 2003, Journal of biomedical materials research. Part B, Applied biomaterials.

[62]  P. Waterhouse,et al.  Marker gene elimination from transgenic barley, using co-transformation with adjacent `twin T-DNAs' on a standard Agrobacterium transformation vector , 2001, Molecular Breeding.

[63]  D. Schubert,et al.  Silencing in Arabidopsis T-DNA Transformants: The Predominant Role of a Gene-Specific RNA Sensing Mechanism versus Position Effects , 2004, The Plant Cell Online.

[64]  M. Šmehilová,et al.  Genetic transformation of barley: limiting factors , 2011, Biologia Plantarum.

[65]  Shigeru Kamiyama,et al.  Impact of detection of bacterial endotoxin in menstrual effluent on the pregnancy rate in in vitro fertilization and embryo transfer. , 2004, Fertility and sterility.

[66]  P. Lemaux,et al.  Generation of Large Numbers of Independently Transformed Fertile Barley Plants , 1994, Plant physiology.

[67]  W. McKinstry,et al.  Removal of endotoxin by reverse phase HPLC abolishes anti-endothelial cell activity of bacterially expressed plasminogen kringle 5. , 2003, BioTechniques.

[68]  Z. Wang,et al.  LPS induces IL-8 expression through TLR4, MyD88, NF-kappaB and MAPK pathways in human dental pulp stem cells. , 2013, International endodontic journal.

[69]  F. Bootz,et al.  Tissue‐resident mesenchymal stem cells attract peripheral blood neutrophils and enhance their inflammatory activity in response to microbial challenge , 2010, Journal of leukocyte biology.

[70]  A. Nuutila,et al.  Inducing homozygosity in transgenic barley (Hordeum vulgare L.) by microspore culture , 2005, Acta Physiologiae Plantarum.

[71]  R. Kalla,et al.  Agrobacterium tumefaciens‐mediated barley transformation , 1997 .

[72]  Matthias Kraume,et al.  Analyses of polysaccharide fouling mechanisms during crossflow membrane filtration , 2008 .

[73]  R. Madhusudhan.  Plant Cell Cultures for the Production of Phytochemicals - Anthocyanin and Capsaicin in Bioreactors , 1998 .

[74]  Alberto Gianinetti,et al.  A theoretical framework for β-glucan degradation during barley malting , 2009, Theory in Biosciences.

[75]  G. Fincher,et al.  Gene flow from transgenic wheat and barley under field conditions , 2006, Euphytica.

[76]  A. Frizzi,et al.  Tapping RNA silencing pathways for plant biotechnology. , 2010, Plant Biotechnology Journal.

[77]  C. Raetz,et al.  Induction of kappa light chain synthesis in 70Z/3 B lymphoma cells by chemically defined lipid A precursors. , 1988, The Journal of biological chemistry.

[78]  S. Ullrich,et al.  Barley for food: Characteristics, improvement, and renewed interest , 2008 .

[79]  M. Paul,et al.  Plant‐made pharmaceuticals: Leading products and production platforms , 2011, Biotechnology and applied biochemistry.

[80]  O. Lau,et al.  Plant seeds as bioreactors for recombinant protein production. , 2009, Biotechnology advances.

[81]  J. Delcour,et al.  The effects of malting and mashing on barley protein extractability , 2006 .

[82]  X. Fang,et al.  Atorvastatin reduces lipopolysaccharide-induced expression of cyclooxygenase-2 in human pulmonary epithelial cells , 2005, Respiratory research.

[83]  Fei-bo Wu,et al.  Protein Fractions in Barley Grains as Affected by Some Agronomic Factors and Their Relationships to Malt Quality , 2007 .

[84]  L. Moldawer,et al.  Endotoxin-induced production of interleukin 6 by equine peritoneal macrophages in vitro. , 1992, American journal of veterinary research.

[85]  J. Kumlehn,et al.  Efficient generation of transgenic barley: the way forward to modulate plant-microbe interactions. , 2008, Journal of plant physiology.

[86]  F. B. Anspach,et al.  Removal of endotoxins by affinity sorbents. , 1995, Journal of chromatography. A.

[87]  B. Finlay,et al.  Lipopolysaccharide induces apoptosis in a bovine endothelial cell line via a soluble CD14 dependent pathway. , 1998, Microbial pathogenesis.

[88]  I. Rubio-Somoza,et al.  The DOF protein, SAD, interacts with GAMYB in plant nuclei and activates transcription of endosperm-specific genes during barley seed development. , 2005, The Plant journal : for cell and molecular biology.

[89]  D. Douchkov,et al.  A Set of Modular Binary Vectors for Transformation of Cereals1[W][OA] , 2007, Plant Physiology.

[90]  Z. Yin,et al.  Evaluation of seed storage protein gene 3′-untranslated regions in enhancing gene expression in transgenic rice seed , 2011, Transgenic Research.

[91]  P. Christou,et al.  Molecular pharming in cereal crops , 2008, Phytochemistry Reviews.

[92]  B. Jones.  The endogenous endoprotease inhibitors of barley and malt and their roles in malting and brewing , 2005 .

[93]  Nan Li,et al.  TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. , 2007, Molecular immunology.

[94]  Shibo Zhang,et al.  Transgenic Cereals: Hordeum vulgare L. (barley) , 1999 .

[95]  Rainer Fischer,et al.  Plant-based production of biopharmaceuticals. , 2004, Current opinion in plant biology.

[96]  Peter H. Raven,et al.  Biology of plants , 1976 .

[97]  P. Shewry,et al.  The control of protein synthesis in developing barley seeds. , 1992 .

[98]  T. Vanek,et al.  Recombinant Cytokines from Plants , 2011, International journal of molecular sciences.

[99]  M. Penttilä,et al.  Recent advances in the malting and brewing industry1Based on a lecture held at the symposium `Biotechnology in advanced food and feed processing', at the 8th European Congress on Biotechnology (ECB8) in Budapest, Hungary, August 1997.1 , 1998 .

[100]  P. Petersen,et al.  Endotoxins affect bioactivity of chitosan derivatives in cultures of bone marrow-derived human mesenchymal stem cells. , 2013, Acta biomaterialia.

[101]  M. Tsan,et al.  Endotoxin Contamination in Recombinant Human Heat Shock Protein 70 (Hsp70) Preparation Is Responsible for the Induction of Tumor Necrosis Factor α Release by Murine Macrophages* , 2003, The Journal of Biological Chemistry.

[102]  E. Egelkrout.  Overproduction of recombinant proteins in plants , 2013 .

[103]  J. Rinehart,et al.  Effects of endotoxin on proliferation of human hematopoietic cell precursors , 1997, Cytotechnology.

[104]  G. Galili,et al.  6. Novel enzyme replacement therapy for Gaucher disease: On-going phase III clinical trial with recombinant human glucocerebrosidase expressed in plant cells , 2008 .

[105]  S. Sk.  Endotoxin detection and elimination in biotechnology. , 1986 .

[106]  R. Bretzel,et al.  Endotoxin impairs the engraftment of rat islets transplanted beneath the kidney capsule of C57BL/6-mice , 1999, Journal of Molecular Medicine.

[107]  S. Sharma,et al.  Endotoxin detection and elimination in biotechnology. , 1986, Biotechnology and applied biochemistry.

[108]  T. Close.  Dehydrins: Emergence of a biochemical role of a family of plant dehydration proteins , 1996 .

[109]  W. Powell,et al.  Molecular barley breeding , 2007, Euphytica.

[110]  F B Anspach,et al.  Endotoxin removal from protein solutions. , 2000, Journal of biotechnology.

[111]  L. Garrod.  Structure of Bacteria , 1950 .

[112]  W. A. Harwood,et al.  A comparison of transgenic barley lines produced by particle bombardment and Agrobacterium-mediated techniques , 2005, Plant Cell Reports.

[113]  Production of human growth hormone in transgenic rice seeds: co-introduction of RNA interference cassette for suppressing the gene expression of endogenous storage proteins , 2012, Plant Cell Reports.

[114]  H. Rolletschek,et al.  Molecular physiology and genomics of developing barley grains. , 2005 .

[115]  J. Tammisola,et al.  Measuring Gene Flow in the Cultivation of Transgenic Barley. , 2002, Crop science.

[116]  TAL effector nucleases induce mutations at a pre-selected location in the genome of primary barley transformants , 2013, Plant Molecular Biology.

[117]  A. Furtado,et al.  Analysis of promoters in transgenic barley and wheat. , 2009, Plant biotechnology journal.

[118]  A. U. Daniels,et al.  Macrophage cytokine response to particles and lipopolysaccharide in vitro. , 2000, Journal of biomedical materials research.

[119]  Claire A. Penney,et al.  Evolution of Plant-Made Pharmaceuticals , 2011, International journal of molecular sciences.