Bioluminescence imaging: looking beyond the light.

Bioluminescence imaging (BLI) enables in vivo imaging of molecular and cellular processes. It has gained in popularity over the past decade because of its easy translation from in vitro to in vivo experiments, its sensitivity, and its ease of use. However, experience in applying BLI in living subjects is still limited, and many researchers have encountered unexpected or biased BLI readout and reported important influencing factors. In this review, we summarize both the biological and physical effects that occur at the enzyme level or during light propagation towards the camera. The knowledge and detection of such factors, together with the development of new strategies and better BLI compounds, will improve the accuracy of the technique in the future.

[1]  A. Melcher,et al.  Radiation-Mediated Up-Regulation of Gene Expression from Replication-Defective Adenoviral Vectors: Implications for Sodium Iodide Symporter Gene Therapy , 2008, Clinical Cancer Research.

[2]  D. Klaubert,et al.  Noninvasive molecular imaging of apoptosis in vivo using a modified firefly luciferase substrate, Z-DEVD-aminoluciferin , 2010, Cell Death and Differentiation.

[3]  C. Vanhove,et al.  Plasma Protein Binding of Luciferase Substrates Influences Sensitivity and Accuracy of Bioluminescence Imaging , 2011, Molecular Imaging and Biology.

[4]  Sang-Woo Lee,et al.  Evaluation of the Reversal of Multidrug Resistance by MDR1 Ribonucleic Acid Interference in a Human Colon Cancer Model Using a Renilla Luciferase Reporter Gene and Coelenterazine , 2010, Molecular imaging.

[5]  Masafumi Oshiro,et al.  Visualizing Gene Expression in Living Mammals Using a Bioluminescent Reporter , 1997, Photochemistry and photobiology.

[6]  Jinha M. Park,et al.  Effects of epigenetic modulation on reporter gene expression: implications for stem cell imaging , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[7]  I. Weissman,et al.  Imaging of STAT3 signaling pathway during mouse embryonic stem cell differentiation. , 2009, Stem cells and development.

[8]  Wan-Wan Lin,et al.  Proteasome inhibitors stimulate activator protein‐1 pathway via reactive oxygen species production , 2002, FEBS letters.

[9]  Adel Bakhtiarova,et al.  Resveratrol inhibits firefly luciferase. , 2006, Biochemical and biophysical research communications.

[10]  Yusuke Inoue,et al.  Comparison of subcutaneous and intraperitoneal injection of d-luciferin for in vivo bioluminescence imaging , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[11]  M. Bednarski,et al.  The effect of high intensity focused ultrasound on luciferase activity on two tumor cell lines in vitro, under the control of a CMV promoter. , 2009, Ultrasonics.

[12]  W. R. Lieb,et al.  Mechanisms of general anesthesia. , 1990, Environmental health perspectives.

[13]  V. Khankaldyyan,et al.  In Vivo Testing of Renilla Luciferase Substrate Analogs in an Orthotopic Murine Model of Human Glioblastoma , 2006, Molecular imaging.

[14]  Zeger Debyser,et al.  Noninvasive and Quantitative Monitoring of Adult Neuronal Stem Cell Migration in Mouse Brain Using Bioluminescence Imaging , 2008, Stem cells.

[15]  Daniel E. Hall,et al.  Rapid and quantitative assessment of cancer treatment response using in vivo bioluminescence imaging. , 2000, Neoplasia.

[16]  P. Ravassard,et al.  Quantitative Comparison of Constitutive Promoters in Human ES cells , 2010, PloS one.

[17]  R. Svensson,et al.  Chemotherapeutic agents up-regulate the cytomegalovirus promoter: implications for bioluminescence imaging of tumor response to therapy. , 2007, Cancer research.

[18]  Jianghong Rao,et al.  In vivo bioluminescence imaging of furin activity in breast cancer cells using bioluminogenic substrates. , 2009, Bioconjugate chemistry.

[19]  Shingo Baba,et al.  How Reproducible Is Bioluminescent Imaging of Tumor Cell Growth? Single Time Point versus the Dynamic Measurement Approach , 2007, Molecular imaging.

[20]  C. Johnson,et al.  A bioluminescence resonance energy transfer (BRET) system: application to interacting circadian clock proteins. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  E Duco Jansen,et al.  Validation of bioluminescent imaging techniques. , 2009, Methods in molecular biology.

[22]  Christopher H Contag,et al.  Characterization of coelenterazine analogs for measurements of Renilla luciferase activity in live cells and living animals. , 2004, Molecular imaging.

[23]  Sanjiv Sam Gambhir,et al.  Red-shifted Renilla reniformis luciferase variants for imaging in living subjects , 2007, Nature Methods.

[24]  Katherine W. Calabro,et al.  Temporal Variations of Skin Pigmentation in C57Bl/6 Mice Affect Optical Bioluminescence Quantitation , 2010, Molecular Imaging and Biology.

[25]  C. Vanhove,et al.  Correlation Between Epidermal Growth Factor Receptor-Specific Nanobody Uptake and Tumor Burden: A Tool for Noninvasive Monitoring of Tumor Response to Therapy , 2011, Molecular Imaging and Biology.

[26]  P. Cossart,et al.  Conjugated action of two species-specific invasion proteins for fetoplacental listeriosis , 2008, Nature.

[27]  B. Blagg,et al.  High-throughput assay for the identification of Hsp90 inhibitors based on Hsp90-dependent refolding of firefly luciferase. , 2007, Bioorganic & medicinal chemistry.

[28]  C. Contag,et al.  Emission spectra of bioluminescent reporters and interaction with mammalian tissue determine the sensitivity of detection in vivo. , 2005, Journal of biomedical optics.

[29]  S. Gambhir,et al.  Molecular imaging in living subjects: seeing fundamental biological processes in a new light. , 2003, Genes & development.

[30]  D. Auld,et al.  Illuminating insights into firefly luciferase and other bioluminescent reporters used in chemical biology. , 2010, Chemistry & biology.

[31]  A. Tsourkas,et al.  Firefly Luciferase and Rluc8 Exhibit Differential Sensitivity to Oxidative Stress in Apoptotic Cells , 2011, PloS one.

[32]  Sanjiv S. Gambhir,et al.  Bioluminescence resonance energy transfer (BRET) imaging of protein–protein interactions within deep tissues of living subjects , 2011, Proceedings of the National Academy of Sciences.

[33]  W. R. Lieb,et al.  Molecular and cellular mechanisms of general anaesthesia , 1994, Nature.

[34]  G. Tozer.  Measuring tumour vascular response to antivascular and antiangiogenic drugs. , 2003, The British journal of radiology.

[35]  Wafik S El-Deiry,et al.  Bioluminescent Molecular Imaging of Endogenous and Exogenous p53-Mediated Transcription In Vitro and In Vivo Using an HCT116 Human Colon Carcinoma Xenograft Model , 2003, Cancer biology & therapy.

[36]  C. Riedel,et al.  Bacterial luciferase reporters: The Swiss army knife of molecular biology , 2011, Bioengineered bugs.

[37]  Julie L Prior,et al.  Imaging reversal of multidrug resistance in living mice with bioluminescence: MDR1 P-glycoprotein transports coelenterazine. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[38]  Christopher H Contag,et al.  Technoreview: In vivo bioluminescence imaging for integrated studies of infection , 2004, Cellular microbiology.

[39]  D. Piwnica-Worms,et al.  Spying on cancer: molecular imaging in vivo with genetically encoded reporters. , 2005, Cancer cell.

[40]  N. Perkins,et al.  The p53-inhibitor Pifithrin-α inhibits Firefly Luciferase activity in vivo and in vitro , 2003, BMC Molecular Biology.

[41]  J. Capeau,et al.  Haemoglobin interferes with the ex vivo luciferase luminescence assay: consequence for detection of luciferase reporter gene expression in vivo , 2000, Gene Therapy.

[42]  Christopher H Contag,et al.  Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. , 2003, Blood.

[43]  M. Pomper,et al.  ABCG2/BCRP expression modulates D-Luciferin based bioluminescence imaging. , 2007, Cancer research.

[44]  F. Baneyx,et al.  A set of multicolored Photinus pyralis luciferase mutants for in vivo bioluminescence applications. , 2005, Protein engineering, design & selection : PEDS.

[45]  Mathias Hoehn,et al.  In Vivo Optical Imaging of Neurogenesis: Watching New Neurons in the Intact Brain , 2008, Molecular imaging.

[46]  G. Brightwell,et al.  Serum-dependent and cell cycle-dependent expression from a cytomegalovirus-based mammalian expression vector. , 1997, Gene.

[47]  G. Luker,et al.  Real-time bioluminescence imaging of viral pathogenesis. , 2009, Methods in molecular biology.

[48]  Alnawaz Rehemtulla,et al.  Noninvasive Imaging of Apoptosis and Its Application in Cancer Therapeutics , 2008, Clinical Cancer Research.

[49]  Peter P. Antich,et al.  Validating Bioluminescence Imaging as a High-Throughput, Quantitative Modality for Assessing Tumor Burden , 2004 .

[50]  C. Landry,et al.  Quantification of dynamic protein complexes using Renilla luciferase fragment complementation applied to protein kinase A activities in vivo , 2007, Proceedings of the National Academy of Sciences.

[51]  W. D. Martin,et al.  A luciferase transgenic mouse model: visualization of prostate development and its androgen responsiveness in live animals. , 2005, Journal of molecular endocrinology.

[52]  C. Contag,et al.  Noninvasive assessment of tumor cell proliferation in animal models. , 1999, Neoplasia.

[53]  Christopher H Contag,et al.  Guided by the light: visualizing biomolecular processes in living animals with bioluminescence. , 2010, Current opinion in chemical biology.

[54]  Alnawaz Rehemtulla,et al.  Molecular imaging of Akt kinase activity , 2007, Nature Medicine.

[55]  Whole‐Body Imaging of Infection Using Bioluminescence , 2011, Current protocols in microbiology.

[56]  W. Bruening,et al.  Activation of stress-activated MAP protein kinases up-regulates expression of transgenes driven by the cytomegalovirus immediate/early promoter. , 1998, Nucleic acids research.

[57]  A. Bossuyt,et al.  Inhibition of Firefly Luciferase by General Anesthetics: Effect on In Vitro and In Vivo Bioluminescence Imaging , 2012, PloS one.

[58]  Takahiro Kimura,et al.  Optimization of enzyme–substrate pairing for bioluminescence imaging of gene transfer using Renilla and Gaussia luciferases , 2010, The journal of gene medicine.

[59]  B. Comin-Anduix,et al.  Kinetic phases of distribution and tumor targeting by T cell receptor engineered lymphocytes inducing robust antitumor responses , 2010, Proceedings of the National Academy of Sciences.

[60]  L. Lilge,et al.  The influence of hypoxia on bioluminescence in luciferase-transfected gliosarcoma tumor cells in vitro , 2008, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[61]  J. Engelhardt,et al.  Indexing TNF-α gene expression using a gene-targeted reporter cell line , 2009, BMC Biology.

[62]  O. Shimomura,et al.  The use of Renilla luciferase, Oplophorus luciferase, and apoaequorin as bioluminescent reporter protein in the presence of coelenterazine analogues as substrate. , 1997, Biochemical and biophysical research communications.

[63]  V. Thulasiraman,et al.  Effect of geldanamycin on the kinetics of chaperone-mediated renaturation of firefly luciferase in rabbit reticulocyte lysate. , 1996, Biochemistry.

[64]  S. Gambhir,et al.  Optical imaging of Renilla luciferase reporter gene expression in living mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[65]  G. Sayler,et al.  Autonomous Bioluminescent Expression of the Bacterial Luciferase Gene Cassette (lux) in a Mammalian Cell Line , 2010, PloS one.

[66]  B. Deroo,et al.  Proteasome Inhibitors Reduce Luciferase and β-Galactosidase Activity in Tissue Culture Cells* , 2002, The Journal of Biological Chemistry.

[67]  R. Blasberg.  Molecular imaging and cancer. , 2003, Molecular cancer therapeutics.

[68]  I. Ueda.  Effects of Diethyl Ether and Halothane on Firefly Luciferin Bioluminescence , 1965, Anesthesiology.

[69]  Y. Minami,et al.  Hsc70/Hsp40 chaperone system mediates the Hsp90‐dependent refolding of firefly luciferase , 1999, Genes to cells : devoted to molecular & cellular mechanisms.

[70]  P. Sutphin,et al.  Oxygen Sensitivity of Reporter Genes: Implications for Preclinical Imaging of Tumor Hypoxia , 2007, Molecular imaging.

[71]  Christopher P Austin,et al.  Characterization of chemical libraries for luciferase inhibitory activity. , 2008, Journal of medicinal chemistry.

[72]  E. Jansen,et al.  Factors Influencing Quantification of in Vivo Bioluminescence Imaging: Application to Assessment of Pancreatic Islet Transplants , 2004 .

[73]  Jianghong Rao,et al.  Biosensing and imaging based on bioluminescence resonance energy transfer. , 2009, Current opinion in biotechnology.

[74]  Marleen Keyaerts,et al.  Dynamic bioluminescence imaging for quantitative tumour burden assessment using IV or IP administration of d-luciferin: effect on intensity, time kinetics and repeatability of photon emission , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[75]  J. Devincenzo,et al.  Determination of picogram amounts of ATP using the luciferin-luciferase enzyme system. , 1967, Analytical biochemistry.