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New imaging probes to track cell fate: reporter genes in stem cell research

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Abstract

Cell fate is a concept used to describe the differentiation and development of a cell in its organismal context over time. It is important in the field of regenerative medicine, where stem cell therapy holds much promise but is limited by our ability to assess its efficacy, which is mainly due to the inability to monitor what happens to the cells upon engraftment to the damaged tissue. Currently, several imaging modalities can be used to track cells in the clinical setting; however, they do not satisfy many of the criteria necessary to accurately assess several aspects of cell fate. In recent years, reporter genes have become a popular option for tracking transplanted cells, via various imaging modalities in small mammalian animal models. This review article examines the reporter gene strategies used in imaging modalities such as MRI, SPECT/PET, Optoacoustic and Bioluminescence Imaging. Strengths and limitations of the use of reporter genes in each modality are discussed.

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References

  1. Aarntzen EH, Srinivas M, Walczak P, Janowski M, Heerschap A, de Vries IJ, Figdor CG, Bulte JW, Oyen WJ (2012) In vivo tracking techniques for cellular regeneration, replacement, and redirection. J Nucl Med 53(12):1825–1828. doi:10.2967/jnumed.112.106146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Leahy M, Thompson K, Zafar H, Alexandrov S, Foley M, O’Flatharta C, Dockery P (2016) Functional imaging for regenerative medicine. Stem Cell Res Ther 7(1):57. doi:10.1186/s13287-016-0315-2

    Article  PubMed  PubMed Central  Google Scholar 

  3. Su W, Leng L, Han Z, He Z, Li Z (2013) Bioluminescence imaging of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction. Methods Mol Biol 1052:203–215. doi:10.1007/7651_2013_15

    Article  CAS  PubMed  Google Scholar 

  4. Yu Q, Fan W, Cao F (2013) Mechanistic molecular imaging of cardiac cell therapy for ischemic heart disease. Am J Physiol Heart Circ Physiol 305(7):H947–H959. doi:10.1152/ajpheart.00092.2013

    Article  CAS  PubMed  Google Scholar 

  5. Chen IY, Wu JC (2013) Molecular imaging: the key to advancing cardiac stem cell therapy. Trends Cardiovasc Med 23(6):201–210. doi:10.1016/j.tcm.2012.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Naumova AV, Modo M, Moore A, Murry CE, Frank JA (2014) Clinical imaging in regenerative medicine. Nat Biotechnol 32(8):804–818. doi:10.1038/nbt.2993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nolta JA (2015) New advances in understanding stem cell fate and function. Stem Cells 33(2):313–315. doi:10.1002/stem.1905

    Article  PubMed  Google Scholar 

  8. Ronald JA, Cusso L, Chuang HY, Yan X, Dragulescu-Andrasi A, Gambhir SS (2013) Development and validation of non-integrative, self-limited, and replicating minicircles for safe reporter gene imaging of cell-based therapies. PLoS One 8(8):e73138. doi:10.1371/journal.pone.0073138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wang J, Jokerst JV (2016) Stem cell imaging: tools to improve cell delivery and viability. Stem Cells Int 2016:9240652. doi:10.1155/2016/9240652

    PubMed  PubMed Central  Google Scholar 

  10. Cromer Berman SM, Walczak P, Bulte JW (2011) Tracking stem cells using magnetic nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol 3(4):343–355. doi:10.1002/wnan.140

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Vande Velde G, Himmelreich U, Neeman M (2013) Reporter gene approaches for mapping cell fate decisions by MRI: promises and pitfalls. Contrast Media Mol Imaging 8(6):424–431. doi:10.1002/cmmi.1590

    Article  CAS  PubMed  Google Scholar 

  12. Vandsburger M (2014) Cardiac cell tracking with MRI reporter genes: welcoming a new field. Curr Cardiovasc Imaging Rep 7:9250. doi:10.1007/s12410-013-9250-0

    Article  PubMed  PubMed Central  Google Scholar 

  13. Cho IK, Moran SP, Paudyal R, Piotrowska-Nitsche K, Cheng PH, Zhang X, Mao H, Chan AW (2014) Longitudinal monitoring of stem cell grafts in vivo using magnetic resonance imaging with inducible maga as a genetic reporter. Theranostics 4(10):972–989. doi:10.7150/thno.9436

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Chung J, Kee K, Barral JK, Dash R, Kosuge H, Wang X, Weissman I, Robbins RC, Nishimura D, Quertermous T, Reijo-Pera RA, Yang PC (2011) In vivo molecular MRI of cell survival and teratoma formation following embryonic stem cell transplantation into the injured murine myocardium. Mag Reson Med 66(5):1374–1381. doi:10.1002/mrm.22929

    Article  Google Scholar 

  15. Srivastava AK, Bulte JW (2014) Seeing stem cells at work in vivo. Stem Cell Rev 10(1):127–144. doi:10.1007/s12015-013-9468-x

    Article  PubMed  PubMed Central  Google Scholar 

  16. Pereira SM, Moss D, Williams SR, Murray P, Taylor A (2015) Overexpression of the MRI reporter genes ferritin and transferrin receptor affect iron homeostasis and produce limited contrast in mesenchymal stem cells. Int J Mol Sci 16(7):15481–15496. doi:10.3390/ijms160715481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kaur D, Rajagopalan S, Chinta S, Kumar J, Di Monte D, Cherny RA, Andersen JK (2007) Chronic ferritin expression within murine dopaminergic midbrain neurons results in a progressive age-related neurodegeneration. Brain Res 1140:188–194. doi:10.1016/j.brainres.2006.03.006

    Article  CAS  PubMed  Google Scholar 

  18. Bartelle BB, Szulc KU, Suero-Abreu GA, Rodriguez JJ, Turnbull DH (2013) Divalent metal transporter, DMT1: a novel MRI reporter protein. Magn Reson Med 70(3):842–850. doi:10.1002/mrm.24509

    Article  PubMed  CAS  Google Scholar 

  19. Gilad A, McMahon M, Walczak P, Winnard P, Raman V, van Laarhoven H, Skoglund C, Bulte J, van Zijl P (2007) Artificial reporter gene providing MRI contrast based on proton exchange. Nat Biotechnol 25(2):217–219. doi:10.1038/nbt1277

    Article  CAS  PubMed  Google Scholar 

  20. Airan RD, Bar-Shir A, Liu G, Pelled G, McMahon MT, Zijl PCMV, Bulte JWM, Gilad AA (2012) MRI biosensor for protein kinase A encoded by a single synthetic gene. Magn Reson Med 68(6):1919–1923. doi:10.1002/mrm.24483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bar-Shir A, Liang Y, Chan KW, Gilad AA, Bulte JW (2015) Supercharged green fluorescent proteins as bimodal reporter genes for CEST MRI and optical imaging. Chem Commun (Camb) 51(23):4869–4871. doi:10.1039/c4cc10195b

    Article  CAS  Google Scholar 

  22. Bar-Shir A, Liu G, Chan KW, Oskolkov N, Song X, Yadav NN, Walczak P, McMahon MT, van Zijl PC, Bulte JW, Gilad AA (2014) Human protamine-1 as an MRI reporter gene based on chemical exchange. ACS Chem Biol 9(1):134–138. doi:10.1021/cb400617q

    Article  CAS  PubMed  Google Scholar 

  23. Bar-Shir A, Liu G, Greenberg MM, Bulte JW, Gilad AA (2013) Synthesis of a probe for monitoring HSV1-tk reporter gene expression using chemical exchange saturation transfer MRI. Nat Protoc 8(12):2380–2391. doi:10.1038/nprot.2013.140

    Article  CAS  PubMed  Google Scholar 

  24. Ferrauto G, Castelli DD, Terreno E, Aime S (2013) In vivo MRI visualization of different cell populations labeled with PARACEST agents. Magn Reson Med 69(6):1703–1711. doi:10.1002/mrm.24411

    Article  CAS  PubMed  Google Scholar 

  25. Shapiro MG, Ramirez RM, Sperling LJ, Sun G, Sun J, Pines A, Schaffer DV, Bajaj VS (2014) Genetically encoded reporters for hyperpolarized xenon magnetic resonance imaging. Nat Chem 6(7):629–634. doi:10.1038/nchem.1934

    Article  CAS  PubMed  Google Scholar 

  26. Kedziorek DA, Solaiyappan M, Walczak P, Ehtiati T, Fu Y, Bulte JW, Shea SM, Brost A, Wacker FK, Kraitchman DL (2013) Using C-arm X-ray imaging to guide local reporter probe delivery for tracking stem cell engraftment. Theranostics 3(11):916–926. doi:10.7150/thno.6943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wolfs E, Holvoet B, Gijsbers R, Casteels C, Roberts SJ, Struys T, Maris M, Ibrahimi A, Debyser Z, Van Laere K, Verfaillie CM, Deroose CM (2014) Optimization of multimodal imaging of mesenchymal stem cells using the human sodium iodide symporter for PET and Cerenkov luminescence imaging. PLoS One 9(4):e94833. doi:10.1371/journal.pone.0094833

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Yaghoubi SS, Campbell DO, Radu CG, Czernin J (2012) Positron emission tomography reporter genes and reporter probes: gene and cell therapy applications. Theranostics 2(4):374–391. doi:10.7150/thno.3677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schönitzer V, Haasters F, Käsbauer S, Ulrich V, Mille E, Gildehaus FJ, Carlsen J, Pape M, Beck R, Delker A, Böning G, Mutschler W, Böcker W, Schieker M, Bartenstein P (2014) In vivo mesenchymal stem cell tracking with PET using the dopamine type 2 receptor and 18F-fallypride. J Nucl Med 55(8):1342–1347. doi:10.2967/jnumed.113.134775

    Article  PubMed  CAS  Google Scholar 

  30. Muñoz-Álvarez KA, Altomonte J, Laitinen I, Ziegler S, Steiger K, Esposito I, Schmid RM, Ebert O (2015) PET imaging of oncolytic VSV expressing the mutant HSV-1 thymidine kinase transgene in a preclinical HCC rat model. Mol Ther 23(4):728–736. doi:10.1038/mt.2015.12

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Gallezot JD, Beaver JD, Gunn RN, Nabulsi N, Weinzimmer D, Singhal T, Slifstein M, Fowles K, Ding YS, Huang Y, Laruelle M, Carson RE, Rabiner EA (2012) Affinity and selectivity of [11C]-(+)-PHNO for the D3 and D2 receptors in the rhesus monkey brain in vivo. Synapse 66(6):489–500. doi:10.1002/syn.21535

    Article  CAS  PubMed  Google Scholar 

  32. Aung W, Okauchi T, Sato M, Saito T, Nakagawa H, Ishihara H, Ikota N, Suhara T, Anzai K (2005) In-vivo PET imaging of inducible D2R reporter transgene expression using [11C]FLB 457 as reporter probe in living rats. Nucl Med Commun 26(3):259–268

    Article  CAS  PubMed  Google Scholar 

  33. Moroz MA, Zhang H, Lee J, Moroz E, Zurita J, Shenker L, Serganova I, Blasberg R, Ponomarev V (2015) Comparative analysis of T cell imaging with human nuclear reporter genes. J Nucl Med 56(7):1055–1060. doi:10.2967/jnumed.115.159855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Doubrovin MM, Doubrovina ES, Zanzonico P, Sadelain M, Larson SM, O’Reilly RJ (2007) In vivo imaging and quantitation of adoptively transferred human antigen-specific T cells transduced to express a human norepinephrine transporter gene. Cancer Res 67(24):11959–11969. doi:10.1158/0008-5472.CAN-07-1250

    Article  CAS  PubMed  Google Scholar 

  35. Hu S, Cao W, Lan X, He Y, Lang J, Li C, Hu J, An R, Gao Z, Zhang Y (2011) Comparison of rNIS and hNIS as reporter genes for noninvasive imaging of bone mesenchymal stem cells transplanted into infarcted rat myocardium. Mol Imaging 10(4):227–237. doi:10.2310/7290.2010.00051

    CAS  PubMed  Google Scholar 

  36. Micci MA, Boone DR, Parsley MA, Wei J, Patrikeev I, Motamedi M, Hellmich HL (2015) Development of a novel imaging system for cell therapy in the brain. Stem Cell Res Ther 6:131. doi:10.1186/s13287-015-0129-7

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Acton PD, Zhou R (2005) Imaging reporter genes for cell tracking with PET and SPECT. Q J Nucl Med Mol Imaging 49(4):349–360

    CAS  PubMed  Google Scholar 

  38. Contag CH, Contag PR, Mullins JI, Spilman SD, Stevenson DK, Benaron DA (1995) Photonic detection of bacterial pathogens in living hosts. Mol Microbiol 18(4):593–603

    Article  CAS  PubMed  Google Scholar 

  39. Contag CH, Bachmann MH (2002) Advances in in vivo bioluminescence imaging of gene expression. Annu Rev Biomed Eng 4:235–260. doi:10.1146/annurev.bioeng.4.111901.093336

    Article  CAS  PubMed  Google Scholar 

  40. Wilson K, Yu J, Lee A, Wu JC (2008) In vitro and in vivo bioluminescence reporter gene imaging of human embryonic stem cells. J Vis Exp. doi:10.3791/740

    PubMed  PubMed Central  Google Scholar 

  41. Prescher JA, Contag CH (2010) Guided by the light: visualizing biomolecular processes in living animals with bioluminescence. Curr Opin Chem Biol 14(1):80–89. doi:10.1016/j.cbpa.2009.11.001

    Article  CAS  PubMed  Google Scholar 

  42. Liang Y, Walczak P, Bulte JW (2012) Comparison of red-shifted firefly luciferase Ppy RE9 and conventional Luc2 as bioluminescence imaging reporter genes for in vivo imaging of stem cells. J Biomed Opt 17(1):016004. doi:10.1117/1.JBO.17.1.016004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Kim JB, Urban K, Cochran E, Lee S, Ang A, Rice B, Bata A, Campbell K, Coffee R, Gorodinsky A, Lu Z, Zhou H, Kishimoto TK, Lassota P (2010) Non-invasive detection of a small number of bioluminescent cancer cells in vivo. PLoS One 5(2):e9364. doi:10.1371/journal.pone.0009364

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Zhao H, Doyle TC, Coquoz O, Kalish F, Rice BW, Contag CH (2005) Emission spectra of bioluminescent reporters and interaction with mammalian tissue determine the sensitivity of detection in vivo. J Biomed Opt 10(4):41210. doi:10.1117/1.2032388

    Article  PubMed  CAS  Google Scholar 

  45. Rice BW, Contag CH (2009) The importance of being red. Nat Biotechnol 27(7):624–625. doi:10.1038/nbt0709-624

    Article  CAS  PubMed  Google Scholar 

  46. Mezzanotte L, Aswendt M, Tennstaedt A, Hoeben R, Hoehn M, Löwik C (2013) Evaluating reporter genes of different luciferases for optimized in vivo bioluminescence imaging of transplanted neural stem cells in the brain. Contrast Media Mol Imaging 8(6):505–513. doi:10.1002/cmmi.1549

    Article  CAS  PubMed  Google Scholar 

  47. Rumyantsev KA, Turoverov KK, Verkhusha VV (2016) Near-infrared bioluminescent proteins for two-color multimodal imaging. Sci Rep 6:36588. doi:10.1038/srep36588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Conley NR, Dragulescu-Andrasi A, Rao J, Moerner WE (2012) A selenium analogue of firefly d-luciferin with red-shifted bioluminescence emission. Angew Chem Int Ed Engl 51(14):3350–3353. doi:10.1002/anie.201105653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mofford DM, Reddy GR, Miller SC (2014) Aminoluciferins extend firefly luciferase bioluminescence into the near-infrared and can be preferred substrates over d-luciferin. J Am Chem Soc 136(38):13277–13282. doi:10.1021/ja505795s

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jathoul AP, Grounds H, Anderson JC, Pule MA (2014) A dual-color far-red to near-infrared firefly luciferin analogue designed for multiparametric bioluminescence imaging. Angew Chem Int Ed Engl 53(48):13059–13063. doi:10.1002/anie.201405955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Steinhardt RC, O’Neill JM, Rathbun CM, McCutcheon DC, Paley MA, Prescher JA (2016) Design and synthesis of an alkynyl luciferin analogue for bioluminescence imaging. Chemistry 22(11):3671–3675. doi:10.1002/chem.201503944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kuchimaru T, Iwano S, Kiyama M, Mitsumata S, Kadonosono T, Niwa H, Maki S, Kizaka-Kondoh S (2016) A luciferin analogue generating near-infrared bioluminescence achieves highly sensitive deep-tissue imaging. Nat Commun 7:11856. doi:10.1038/ncomms11856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kiyama M, Saito R, Iwano S, Obata R, Niwa H, Maki SA (2016) Multicolor bioluminescence obtained using firefly luciferin. Curr Top Med Chem 16(24):2648–2655

    Article  CAS  PubMed  Google Scholar 

  54. Wu W, Su J, Tang C, Bai H, Ma Z, Zhang T, Yuan Z, Li Z, Zhou W, Zhang H, Liu Z, Wang Y, Zhou Y, Du L, Gu L, Li M (2017) cybLuc: an effective aminoluciferin derivative for deep bioluminescence imaging. Anal Chem 89(9):4808–4816. doi:10.1021/acs.analchem.6b03510

    Article  CAS  PubMed  Google Scholar 

  55. Adams ST, Miller SC (2014) Beyond D-luciferin: expanding the scope of bioluminescence imaging in vivo. Curr Opin Chem Biol 21:112–120. doi:10.1016/j.cbpa.2014.07.003

    Article  CAS  PubMed  Google Scholar 

  56. Kim JE, Kalimuthu S, Ahn BC (2015) In vivo cell tracking with bioluminescence imaging. Nucl Med Mol Imaging 49(1):3–10. doi:10.1007/s13139-014-0309-x

    Article  CAS  PubMed  Google Scholar 

  57. Loening AM, Dragulescu-Andrasi A, Gambhir SS (2010) A red-shifted Renilla luciferase for transient reporter-gene expression. Nat Methods 7(1):5–6. doi:10.1038/nmeth0110-05

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Rahnama S, Saffar B, Kahrani ZF, Nazari M, Emamzadeh R (2017) Super RLuc8: a novel engineered Renilla luciferase with a red-shifted spectrum and stable light emission. Enzyme Microb Technol 96:60–66. doi:10.1016/j.enzmictec.2016.09.009

    Article  CAS  PubMed  Google Scholar 

  59. Luker KE, Mihalko LA, Schmidt BT, Lewin SA, Ray P, Shcherbo D, Chudakov DM, Luker GD (2011) In vivo imaging of ligand receptor binding with Gaussia luciferase complementation. Nat Med 18(1):172–177. doi:10.1038/nm.2590

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Stacer AC, Nyati S, Moudgil P, Iyengar R, Luker KE, Rehemtulla A, Luker GD (2013) NanoLuc reporter for dual luciferase imaging in living animals. Mol Imaging 12(7):1–13

    PubMed  PubMed Central  Google Scholar 

  61. Chu J, Oh Y, Sens A, Ataie N, Dana H, Macklin JJ, Laviv T, Welf ES, Dean KM, Zhang F, Kim BB, Tang CT, Hu M, Baird MA, Davidson MW, Kay MA, Fiolka R, Yasuda R, Kim DS, Ng HL, Lin MZ (2016) A bright cyan-excitable orange fluorescent protein facilitates dual-emission microscopy and enhances bioluminescence imaging in vivo. Nat Biotechnol 34(7):760–767. doi:10.1038/nbt.3550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Suzuki K, Kimura T, Shinoda H, Bai G, Daniels MJ, Arai Y, Nakano M, Nagai T (2016) Five colour variants of bright luminescent protein for real-time multicolour bioimaging. Nat Commun 7:13718. doi:10.1038/ncomms13718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bakayan A, Vaquero CF, Picazo F, Llopis J (2011) Red fluorescent protein-aequorin fusions as improved bioluminescent Ca2+ reporters in single cells and mice. PLoS One 6(5):e19520. doi:10.1371/journal.pone.0019520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Grinstead KM, Rowe L, Ensor CM, Joel S, Daftarian P, Dikici E, Zingg JM, Daunert S (2016) Red-shifted aequorin variants incorporating non-canonical amino acids: applications in in vivo imaging. PLoS One 11(7):e0158579. doi:10.1371/journal.pone.0158579

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Bagó JR, Soler-Botija C, Casaní L, Aguilar E, Alieva M, Rubio N, Bayes-Genis A, Blanco J (2013) Bioluminescence imaging of cardiomyogenic and vascular differentiation of cardiac and subcutaneous adipose tissue-derived progenitor cells in fibrin patches in a myocardium infarct model. Int J Cardiol 169(4):288–295. doi:10.1016/j.ijcard.2013.09.013

    Article  PubMed  Google Scholar 

  66. Lee S, Youn H, Chung T, Hwang DW, Oh SW, Kang KW, Chung JK, Lee DS (2014) In vivo bioluminescence imaging of transplanted mesenchymal stem cells as a potential source for pancreatic regeneration. Mol Imaging. doi:10.2310/7290.2014.00023

    PubMed Central  Google Scholar 

  67. Oh HJ, Hwang DW, Youn H, Lee DS (2013) In vivo bioluminescence reporter gene imaging for the activation of neuronal differentiation induced by the neuronal activator neurogenin 1 (Ngn1) in neuronal precursor cells. Eur J Nucl Med Mol Imaging 40(10):1607–1617. doi:10.1007/s00259-013-2457-0

    Article  PubMed  Google Scholar 

  68. Jones KA, Porterfield WB, Rathbun CM, McCutcheon DC, Paley MA, Prescher JA (2017) Orthogonal luciferase-luciferin pairs for bioluminescence imaging. J Am Chem Soc 139(6):2351–2358. doi:10.1021/jacs.6b11737

    Article  CAS  PubMed  Google Scholar 

  69. Maguire CA, Bovenberg MS, Crommentuijn MH, Niers JM, Kerami M, Teng J, Sena-Esteves M, Badr CE, Tannous BA (2013) Triple bioluminescence imaging for in vivo monitoring of cellular processes. Mol Ther Nucleic Acids 2:e99. doi:10.1038/mtna.2013.25

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Aswendt M, Adamczak J, Tennstaedt A (2014) A review of novel optical imaging strategies of the stroke pathology and stem cell therapy in stroke. Front Cell Neurosci 8:226. doi:10.3389/fncel.2014.00226

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Tung JK, Berglund K, Gutekunst CA, Hochgeschwender U, Gross RE (2016) Bioluminescence imaging in live cells and animals. Neurophotonics 3(2):025001. doi:10.1117/1.NPh.3.2.025001

    Article  PubMed  PubMed Central  Google Scholar 

  72. Subach FV, Piatkevich KD, Verkhusha VV (2011) Directed molecular evolution to design advanced red fluorescent proteins. Nat Methods 8(12):1019–1026. doi:10.1038/nmeth.1776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Bajar BT, Wang ES, Lam AJ, Kim BB, Jacobs CL, Howe ES, Davidson MW, Lin MZ, Chu J (2016) Improving brightness and photostability of green and red fluorescent proteins for live cell imaging and FRET reporting. Sci Rep 6:20889. doi:10.1038/srep20889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shcherbo D, Merzlyak EM, Chepurnykh TV, Fradkov AF, Ermakova GV, Solovieva EA, Lukyanov KA, Bogdanova EA, Zaraisky AG, Lukyanov S, Chudakov DM (2007) Bright far-red fluorescent protein for whole-body imaging. Nat Methods 4(9):741–746. doi:10.1038/nmeth1083

    Article  CAS  PubMed  Google Scholar 

  75. Shcherbo D, Murphy CS, Ermakova GV, Solovieva EA, Chepurnykh TV, Shcheglov AS, Verkhusha VV, Pletnev VZ, Hazelwood KL, Roche PM, Lukyanov S, Zaraisky AG, Davidson MW, Chudakov DM (2009) Far-red fluorescent tags for protein imaging in living tissues. Biochem J 418(3):567–574. doi:10.1042/BJ20081949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pandelieva AT, Baran MJ, Calderini GF, McCann JL, Tremblay V, Sarvan S, Davey JA, Couture JF, Chica RA (2016) Brighter red fluorescent proteins by rational design of triple-decker motif. ACS Chem Biol 11(2):508–517. doi:10.1021/acschembio.5b00774

    Article  CAS  PubMed  Google Scholar 

  77. Strack RL, Hein B, Bhattacharyya D, Hell SW, Keenan RJ, Glick BS (2009) A rapidly maturing far-red derivative of DsRed-Express2 for whole-cell labeling. Biochemistry 48(35):8279–8281. doi:10.1021/bi900870u

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Piatkevich KD, Malashkevich VN, Morozova KS, Nemkovich NA, Almo SC, Verkhusha VV (2013) Extended Stokes shift in fluorescent proteins: chromophore-protein interactions in a near-infrared TagRFP675 variant. Sci Rep 3:1847. doi:10.1038/srep01847

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Rodriguez EA, Tran GN, Gross LA, Crisp JL, Shu X, Ling JY, Tsien RY (2016) A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein. Nat Methods 13:763–769. doi:10.1038/nmeth.3935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shu X, Royant A, Lin MZ, Aguilera TA, Lev-Ram V, Steinbach PA, Tsien RY (2009) Mammalian expression of infrared fluorescent proteins engineered from a bacterial phytochrome. Science 324(5928):804–807. doi:10.1126/science.1168683

    Article  PubMed  PubMed Central  Google Scholar 

  81. Yu D, Gustafson WC, Han C, Lafaye C, Noirclerc-Savoye M, Ge WP, Thayer DA, Huang H, Kornberg TB, Royant A, Jan LY, Jan YN, Weiss WA, Shu X (2014) An improved monomeric infrared fluorescent protein for neuronal and tumour brain imaging. Nat Commun 5:3626. doi:10.1038/ncomms4626

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Xie BW, Mol IM, Keereweer S, van Beek ER, Que I, Snoeks TJ, Chan A, Kaijzel EL, Löwik CW (2012) Dual-wavelength imaging of tumor progression by activatable and targeting near-infrared fluorescent probes in a bioluminescent breast cancer model. PLoS One 7(2):e31875. doi:10.1371/journal.pone.0031875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Luke GP, Yeager D, Emelianov SY (2012) Biomedical applications of photoacoustic imaging with exogenous contrast agents. Ann Biomed Eng 40(2):422–437. doi:10.1007/s10439-011-0449-4

    Article  PubMed  Google Scholar 

  84. Kollias N, Baqer AH (1987) Absorption mechanisms of human melanin in the visible, 400–720 nm. J Investig Dermatol 89(4):384–388

    Article  CAS  PubMed  Google Scholar 

  85. Zonios G, Dimou A, Bassukas I, Galaris D, Tsolakidis A, Kaxiras E (2008) Melanin absorption spectroscopy: new method for noninvasive skin investigation and melanoma detection. J Biomed Opt 13(1):014017. doi:10.1117/1.2844710

    Article  PubMed  CAS  Google Scholar 

  86. Jathoul AP, Laufer J, Ogunlade O, Treeby B, Cox B, Zhang E, Johnson P, Rizzey AR, Philip B, Marafioti T, Lythgoe MF, Pedley RB, Pule MA, Beard P (2015) Deep in vivo photoacoustic imaging of mammalian tissues using a tyrosinase-based genetic reporter. Nat Photonics 9:239–246. doi:10.1038/nphoton.2015.22

    CAS  Google Scholar 

  87. Filonov GS, Piatkevich KD, Ting LM, Zhang J, Kim K, Verkhusha VV (2011) Bright and stable near-infrared fluorescent protein for in vivo imaging. Nat Biotechnol 29(8):757–761. doi:10.1038/nbt.1918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Liu M, Schmitner N, Sandrian MG, Zabihian B, Hermann B, Salvenmoser W, Meyer D, Drexler W (2013) In vivo three dimensional dual wavelength photoacoustic tomography imaging of the far red fluorescent protein E2-Crimson expressed in adult zebrafish. Biomed Opt Express 4(10):1846–1855. doi:10.1364/BOE.4.001846

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Lakshmanan A, Farhadi A, Nety SP, Lee-Gosselin A, Bourdeau RW, Maresca D, Shapiro MG (2016) Molecular engineering of acoustic protein nanostructures. ACS Nano 10(8):7314–7322. doi:10.1021/acsnano.6b03364

    Article  CAS  PubMed  Google Scholar 

  90. Ray P, Tsien R, Gambhir SS (2007) Construction and validation of improved triple fusion reporter gene vectors for molecular imaging of living subjects. Cancer Res 67(7):3085–3093. doi:10.1158/0008-5472.CAN-06-2402

    Article  CAS  PubMed  Google Scholar 

  91. Lewis CM, Graves SA, Hernandez R, Valdovinos HF, Barnhart TE, Cai W, Meyerand ME, Nickles RJ, Suzuki M (2015) 52Mn production for PET/MRI tracking of human stem cells expressing divalent metal transporter 1 (DMT1). Theranostics 5(3):227–239. doi:10.7150/thno.10185

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Love Z, Wang F, Dennis J, Awadallah A, Salem N, Lin Y, Weisenberger A, Majewski S, Gerson S, Lee Z (2007) Imaging of mesenchymal stem cell transplant by bioluminescence and PET. J Nucl Med 48(12):2011–2020. doi:10.2967/jnumed.107.043166

    Article  PubMed  Google Scholar 

  93. Pei Z, Lan X, Cheng Z, Qin C, Xia X, Yuan H, Ding Z, Zhang Y (2014) Multimodality molecular imaging to monitor transplanted stem cells for the treatment of ischemic heart disease. PLoS One 9(3):e90543. doi:10.1371/journal.pone.0090543

    Article  PubMed  PubMed Central  Google Scholar 

  94. Kircher MF, Gambhir SS, Grimm J (2011) Noninvasive cell-tracking methods. Nat Rev Clin Oncol 8(11):677–688. doi:10.1038/nrclinonc.2011.141

    Article  CAS  PubMed  Google Scholar 

  95. Mukherjee A, Wu D, Davis HC, Shapiro MG (2016) A genetically encoded reporter for diffusion weighted magnetic resonance imaging. BioRxiv. doi:10.1101/037515

    Google Scholar 

  96. Yao L, Berman BP, Farnham PJ (2015) Demystifying the secret mission of enhancers: linking distal regulatory elements to target genes. Crit Rev Biochem Mol Biol 50(6):550–573. doi:10.3109/10409238.2015.1087961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Adam RC, Yang H, Rockowitz S, Larsen SB, Nikolova M, Oristian DS, Polak L, Kadaja M, Asare A, Zheng D, Fuchs E (2015) Pioneer factors govern super-enhancer dynamics in stem cell plasticity and lineage choice. Nature 521(7552):366–370. doi:10.1038/nature14289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Heinz S, Romanoski CE, Benner C, Glass CK (2015) The selection and function of cell type-specific enhancers. Nat Rev Mol Cell Biol 16(3):144–154. doi:10.1038/nrm3949

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Cherry AB, Daley GQ (2013) Reprogrammed cells for disease modeling and regenerative medicine. Annu Rev Med 64:277–290. doi:10.1146/annurev-med-050311-163324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Garrison BS, Yant SR, Mikkelsen JG, Kay MA (2007) Postintegrative gene silencing within the Sleeping Beauty transposition system. Mol Cell Biol 27(24):8824–8833. doi:10.1128/MCB.00498-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Ohlsson H, Karlsson O, Edlund T (1988) A beta-cell-specific protein binds to the two major regulatory sequences of the insulin gene enhancer. Proc Natl Acad Sci USA 85(12):4228–4231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315(6015):115–122

    Article  CAS  PubMed  Google Scholar 

  103. Kuroda A, Rauch TA, Todorov I, Ku HT, Al-Abdullah IH, Kandeel F, Mullen Y, Pfeifer GP, Ferreri K (2009) Insulin gene expression is regulated by DNA methylation. PLoS One 4(9):e6953. doi:10.1371/journal.pone.0006953

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Pagliuca FW, Millman JR, Gürtler M, Segel M, Van Dervort A, Ryu JH, Peterson QP, Greiner D, Melton DA (2014) Generation of functional human pancreatic β cells in vitro. Cell 159(2):428–439. doi:10.1016/j.cell.2014.09.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ameri J, Borup R, Prawiro C, Ramond C, Schachter KA, Scharfmann R, Semb H (2017) Efficient generation of glucose-responsive beta cells from isolated GP2(+) human pancreatic progenitors. Cell Rep 19(1):36–49. doi:10.1016/j.celrep.2017.03.032

    Article  CAS  PubMed  Google Scholar 

  106. Gutierrez GD, Gromada J, Sussel L (2017) Heterogeneity of the pancreatic beta cell. Front Genet 8:22. doi:10.3389/fgene.2017.00022

    Article  PubMed  PubMed Central  Google Scholar 

  107. Broll S, Oumard A, Hahn K, Schambach A, Bode J (2010) Minicircle performance depending on S/MAR-nuclear matrix interactions. J Mol Biol 395(5):950–965. doi:10.1016/j.jmb.2009.11.066

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748.

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Correspondence to Omer Aras.

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Jurgielewicz, P., Harmsen, S., Wei, E. et al. New imaging probes to track cell fate: reporter genes in stem cell research. Cell. Mol. Life Sci. 74, 4455–4469 (2017). https://doi.org/10.1007/s00018-017-2584-z

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  • DOI: https://doi.org/10.1007/s00018-017-2584-z

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