Molecular Considerations in Cell Transplant Imaging

  • Aline M. Thomas
  • Jeff W. M. BulteEmail author
Part of the Molecular and Translational Medicine book series (MOLEMED)


Cell transplantation, similar to organ transplantation, has the ability to provide dynamic treatments to patients that can keep pace with the demands of their lives, yet most cell transplantation therapies do not succeed in treating the patient. Transplant imaging has been developed to explore why cell transplantation can fail as a therapy. However, to date, transplant imaging has primarily focused on potential issues at the cellular level, assessing the number and/or location of transplanted cells present after administration. Lack of survival and migration data are only two of the reasons why cell transplantation can fail as a therapy. Imaging the molecular environment can interrogate the other limitations of candidate therapies: misdirected differentiation, unstable phenotype, reduced functionality, and non-ideal cellular interactions. Detecting these unintended outcomes faster using molecular imaging strategies will allow clinicians to make therapeutic adjustments before failure occurs. More informative imaging strategies will also permit tailoring cell transplants into more robust, patient-specific therapies for personalized medicine.


Molecular imaging Cell tracking MRI PET BLI Regenerative medicine Cancer Transplantation Stem cells 


  1. 1.
    Sekine H, Shimizu T, Dobashi I, Matsuura K, Hagiwara N, Takahashi M, et al. Cardiac cell sheet transplantation improves damaged heart function via superior cell survival in comparison with dissociated cell injection. Tissue Eng Part A. 2011;17(23–24):2973–80.PubMedCrossRefGoogle Scholar
  2. 2.
    Liang Y, Walczak P, Bulte JW. The survival of engrafted neural stem cells within hyaluronic acid hydrogels. Biomaterials. 2013;34(22):5521–9.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Bruin JE, Rezania A, Xu J, Narayan K, Fox JK, O’Neil JJ, et al. Maturation and function of human embryonic stem cell-derived pancreatic progenitors in macroencapsulation devices following transplant into mice. Diabetologia. 2013;56(9):1987–98.PubMedCrossRefGoogle Scholar
  4. 4.
    Dunnett SB, Rosser AE. Clinical translation of cell transplantation in the brain. Curr Opin Organ Transplant. 2011;16(6):632–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Lindvall O. Clinical translation of stem cell transplantation in Parkinson's disease. J Intern Med. 2016;279(1):30–40.PubMedCrossRefGoogle Scholar
  6. 6.
    Goldman SA. Stem and progenitor cell-based therapy of the central nervous system: hopes, hype, and wishful thinking. Cell Stem Cell. 2016;18(2):174–88.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Sellers DL, Maris DO, Horner PJ. Postinjury niches induce temporal shifts in progenitor fates to direct lesion repair after spinal cord injury. J Neurosci. 2009;29(20):6722–33.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Karaca M, Castel J, Tourrel-Cuzin C, Brun M, Géant A, Dubois M, et al. Exploring functional β-cell heterogeneity in vivo using PSA-NCAM as a specific marker. PLoS One. 2009;4(5):e5555.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Huang H-H, Novikova L, Williams SJ, Smirnova IV, Stehno-Bittel L. Low insulin content of large islet population is present in situ and in isolated islets. Islets. 2011;3(1):6–13.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Lehmann R, Zuellig RA, Kugelmeier P, Baenninger PB, Moritz W, Perren A, et al. Superiority of small islets in human islet transplantation. Diabetes. 2007;56(3):594–603.PubMedCrossRefGoogle Scholar
  11. 11.
    Macias MY, Syring MB, Pizzi MA, Crowe MJ, Alexanian AR, Kurpad SN. Pain with no gain: allodynia following neural stem cell transplantation in spinal cord injury. Exp Neurol. 2006;201(2):335–48.PubMedCrossRefGoogle Scholar
  12. 12.
    Aguado BA, Mulyasasmita W, Su J, Lampe KJ, Heilshorn SC. Improving viability of stem cells during syringe needle flow through the design of hydrogel cell carriers. Tissue Eng Part A. 2012;18(7–8):806–15.PubMedCrossRefGoogle Scholar
  13. 13.
    Bennet W, Sundberg B, Groth CG, Brendel MD, Brandhorst D, Brandhorst H, et al. Incompatibility between human blood and isolated islets of langerhans: a finding with implications for clinical intraportal islet transplantation? Diabetes. 1999;48(10):1907–14.PubMedCrossRefGoogle Scholar
  14. 14.
    Moberg L, Korsgren O, Nilsson B. Neutrophilic granulocytes are the predominant cell type infiltrating pancreatic islets in contact with ABO-compatible blood. Clin Exp Immunol. 2005;142(1):125–31.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Manna PP, Hira SK, Das AA, Bandyopadhyay S, Gupta KK. IL-15 activated human peripheral blood dendritic cell kill allogeneic and xenogeneic endothelial cells via apoptosis. Cytokine. 2013;61(1):118–26.PubMedCrossRefGoogle Scholar
  16. 16.
    Pigott JH, Ishihara A, Wellman ML, Russell DS, Bertone AL. Investigation of the immune response to autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses. Vet Immunol Immunopathol. 2013;156(1–2):99–106.PubMedCrossRefGoogle Scholar
  17. 17.
    Amer MH, White LJ, Shakesheff KM. The effect of injection using narrow-bore needles on mammalian cells: administration and formulation considerations for cell therapies. J Pharm Pharmacol. 2015;67(5):640–50.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Jin K, Sun Y, Xie L, Mao XO, Childs J, Peel A, et al. Comparison of ischemia-directed migration of neural precursor cells after intrastriatal, intraventricular, or intravenous transplantation in the rat. Neurobiol Dis. 2005;18(2):366–74.PubMedCrossRefGoogle Scholar
  19. 19.
    Nakamuta JS, Danoviz ME, Marques FLN, dos Santos L, Becker C, Gonçalves GA, et al. Cell therapy attenuates cardiac dysfunction post myocardial infarction: effect of timing, routes of injection and a fibrin scaffold. PLoS One. 2009;4(6):e6005.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Li L, Jiang Q, Ding G, Zhang L, Zhang ZG, Li Q, et al. Effects of administration route on migration and distribution of neural progenitor cells transplanted into rats with focal cerebral ischemia, an MRI study. J Cereb Blood Flow Metab. 2010;30(3):653–62.PubMedCrossRefGoogle Scholar
  21. 21.
    Rocha V, Porcher R, Fernandes JF, Filion A, Bittencourt H, Silva W Jr, et al. Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia. Leukemia. 2008;23(3):545–56.PubMedCrossRefGoogle Scholar
  22. 22.
    Yoo J, Kim H-S, Hwang D-Y. Stem cells as promising therapeutic options for neurological disorders. J Cell Biochem. 2013;114(4):743–53.PubMedCrossRefGoogle Scholar
  23. 23.
    Nishimura S, Yasuda A, Iwai H, Takano M, Kobayashi Y, Nori S, et al. Time-dependent changes in the microenvironment of injured spinal cord affects the therapeutic potential of neural stem cell transplantation for spinal cord injury. Mol Brain. 2013;6(1):3.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Tuinstra HM, Margul DJ, Goodman AG, Boehler RM, Holland SJ, Zelivyanskaya ML, et al. Long-term characterization of axon regeneration and matrix changes using multiple channel bridges for spinal cord regeneration. Tissue Eng Part A. 2014;20(5–6):1027–37.PubMedCrossRefGoogle Scholar
  25. 25.
    Chen J, Leong SY, Schachner M. Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury. Eur J Neurosci. 2005;22(8):1895–906.PubMedCrossRefGoogle Scholar
  26. 26.
    Yamamoto T, Horiguchi A, Ito M, Nagata H, Ichii H, Ricordi C, et al. Quality control for clinical islet transplantation: organ procurement and preservation, the islet processing facility, isolation, and potency tests. J Hepato-Biliary-Pancreat Surg. 2009;16(2):131–6.CrossRefGoogle Scholar
  27. 27.
    Noguchi H, Miyagi-Shiohira C, Kurima K, Kobayashi N, Saitoh I, Watanabe M, et al. Islet culture/preservation before islet transplantation. Cell Med. 2015;8(1–2):25–9.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Noguchi H, Naziruddin B, Jackson A, Shimoda M, Ikemoto T, Fujita Y, et al. Fresh islets are more effective for islet transplantation than cultured islets. Cell Transplant. 2012;21(2–3):517–23.PubMedCrossRefGoogle Scholar
  29. 29.
    Sigrist S, Mechine-Neuville A, Mandes K, Calenda V, Braun S, Legeay G, et al. Influence of VEGF on the viability of encapsulated pancreatic rat islets after transplantation in diabetic mice. Cell Transplant. 2003;12(6):627–35.PubMedCrossRefGoogle Scholar
  30. 30.
    Li X, Chen H, Epstein PN. Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species. J Biol Chem. 2004;279(1):765–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Dufrane D, Goebbels RM, Gianello P. Alginate macroencapsulation of pig islets allows correction of streptozotocin-induced diabetes in primates up to 6 months without immunosuppression. Transplantation. 2010;90(10):1054–62.PubMedCrossRefGoogle Scholar
  32. 32.
    Cardona K, Korbutt GS, Milas Z, Lyon J, Cano J, Jiang W, et al. Long-term survival of neonatal porcine islets in nonhuman primates by targeting costimulation pathways. Nat Med. 2006;12(3):304–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Bellin MD, Sutherland DE, Beilman GJ, Hong-McAtee I, Balamurugan AN, Hering BJ, et al. Similar islet function in islet allotransplant and autotransplant recipients, despite lower islet mass in autotransplants. Transplantation. 2011;91(3):367–72.PubMedCrossRefGoogle Scholar
  34. 34.
    Luo X, Pothoven KL, McCarthy D, DeGutes M, Martin A, Getts DR, et al. ECDI-fixed allogeneic splenocytes induce donor-specific tolerance for long-term survival of islet transplants via two distinct mechanisms. Proc Natl Acad Sci U S A. 2008;105(38):14527–32.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Boks MA, Kager-Groenland JR, Haasjes MSP, Zwaginga JJ, van Ham SM, ten Brinke A. IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction—a comparative study of human clinical-applicable DC. Clin Immunol. 2012;142(3):332–42.PubMedCrossRefGoogle Scholar
  36. 36.
    Thewissen K, Broux B, Hendriks JJ, Vanhees M, Stinissen P, Slaets H, et al. Tolerogenic dendritic cells generated by in vitro treatment with SAHA are not stable in vivo. Cell Transplant. 2016;25(6):1207–18.PubMedCrossRefGoogle Scholar
  37. 37.
    Manavalan JS, Rossi PC, Vlad G, Piazza F, Yarilina A, Cortesini R, et al. High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transpl Immunol. 2003;11(3–4):245–58.PubMedCrossRefGoogle Scholar
  38. 38.
    Wakkach A, Fournier N, Brun V, Breittmayer JP, Cottrez F, Groux H. Characterization of dendritic cells that induce tolerance and T regulatory 1 cell differentiation in vivo. Immunity. 2003;18(5):605–17.PubMedCrossRefGoogle Scholar
  39. 39.
    Park KS, Kim YS, Kim JH, Choi B, Kim SH, Tan AH, et al. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation. 2010;89(5):509–17.PubMedGoogle Scholar
  40. 40.
    Osterhout DJ, Marin-Husstege M, Abano P, Casaccia-Bonnefil P. Molecular mechanisms of enhanced susceptibility to apoptosis in differentiating oligodendrocytes. J Neurosci Res. 2002;69(1):24–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Gard AL, Pfeiffer SE. Two proliferative stages of the oligodendrocyte lineage (A2B5+O4- and O4+GaIC-) under different mitogenic control. Neuron. 1990;5(5):615–25.PubMedCrossRefGoogle Scholar
  42. 42.
    Parr AM, Kulbatski I, Tator CH. Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury. J Neurotrauma. 2007;24(5):835–45.PubMedCrossRefGoogle Scholar
  43. 43.
    Hasegawa K, Chang YW, Li H, Berlin Y, Ikeda O, Kane-Goldsmith N, et al. Embryonic radial glia bridge spinal cord lesions and promote functional recovery following spinal cord injury. Exp Neurol. 2005;193(2):394–410.PubMedCrossRefGoogle Scholar
  44. 44.
    Parr AM, Kulbatski I, Tator CH. Transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury. J Neurotrauma. 2007;24(5):835–45.PubMedCrossRefGoogle Scholar
  45. 45.
    Mazzone PJ, Wang XF, Xu Y, Mekhail T, Beukemann MC, Na J, et al. Exhaled breath analysis with a colorimetric sensor array for the identification and characterization of lung cancer. J Thorac Oncol. 2012;7(1):137–42.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Huo D, Xu Y, Hou C, Yang M, Fa H. A novel optical chemical sensor based AuNR-MTPP and dyes for lung cancer biomarkers in exhaled breath identification. Sensors Actuators B Chem. 2014;199:446–56.CrossRefGoogle Scholar
  47. 47.
    Farrar MJ, Bernstein IM, Schlafer DH, Cleland TA, Fetcho JR, Schaffer CB. Chronic in vivo imaging in the mouse spinal cord using an implanted chamber. Nat Methods. 2012;9(3):297–302.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Horton NG, Wang K, Kobat D, Clark CG, Wise FW, Schaffer CB, et al. In vivo three-photon microscopy of subcortical structures within an intact mouse brain. Nat Photonics. 2013;7(3):205–9.PubMedCentralCrossRefGoogle Scholar
  49. 49.
    Schain AJ, Hill RA, Grutzendler J. Label-free in vivo imaging of myelinated axons in health and disease with spectral confocal reflectance microscopy. Nat Med. 2014;20(4):443–9.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Yusim Y, Livingstone D, Sidi A. Blue dyes, blue people: the systemic effects of blue dyes when administered via different routes. J Clin Anesth. 2007;19(4):315–21.PubMedCrossRefGoogle Scholar
  51. 51.
    Jaffer H, Adjei IM, Labhasetwar V. Optical imaging to map blood-brain barrier leakage. Sci Rep. 2013;3:3117.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Tsoi KM, Dai Q, Alman BA, Chan WCW. Are quantum dots toxic? Exploring the discrepancy between cell culture and animal studies. Acc Chem Res. 2013;46(3):662–71.PubMedCrossRefGoogle Scholar
  53. 53.
    Onoe S, Temma T, Shimizu Y, Ono M, Saji H. Investigation of cyanine dyes for in vivo optical imaging of altered mitochondrial membrane potential in tumors. Cancer Med. 2014;3(4):775–86.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Yuan L, Lin W, Yang Y, Chen H. A unique class of near-infrared functional fluorescent dyes with carboxylic-acid-modulated fluorescence ON/OFF switching: rational design, synthesis, optical properties, theoretical calculations, and applications for fluorescence imaging in living animals. J Am Chem Soc. 2012;134(2):1200–11.PubMedCrossRefGoogle Scholar
  55. 55.
    Komatsu N, Aoki K, Yamada M, Yukinaga H, Fujita Y, Kamioka Y, et al. Development of an optimized backbone of FRET biosensors for kinases and GTPases. Mol Biol Cell. 2011;22(23):4647–56.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Santoso Y, Joyce CM, Potapova O, Le Reste L, Hohlbein J, Torella JP, et al. Conformational transitions in DNA polymerase I revealed by single-molecule FRET. Proc Natl Acad Sci. 2010;107(2):715–20.PubMedCrossRefGoogle Scholar
  57. 57.
    Dennis AM, Rhee WJ, Sotto D, Dublin SN, Bao G. Quantum dot–fluorescent protein FRET probes for sensing intracellular pH. ACS Nano. 2012;6(4):2917–24.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Long L, Lin W, Chen B, Gao W, Yuan L. Construction of a FRET-based ratiometric fluorescent thiol probe. Chem Commun. 2011;47(3):893–5.CrossRefGoogle Scholar
  59. 59.
    Stein IH, Steinhauer C, Tinnefeld P. Single-molecule four-color FRET visualizes energy-transfer paths on DNA origami. J Am Chem Soc. 2011;133(12):4193–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Lam AJ, St-Pierre F, Gong Y, Marshall JD, Cranfill PJ, Baird MA, et al. Improving FRET dynamic range with bright green and red fluorescent proteins. Nat Methods. 2012;9(10):1005–12.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Marras SAE, Kramer FR, Tyagi S. Efficiencies of fluorescence resonance energy transfer and contact-mediated quenching in oligonucleotide probes. Nucleic Acids Res. 2002;30(21):e122.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Li C, Zhang Y, Hu J, Cheng J, Liu S. Reversible three-state switching of multicolor fluorescence emission by multiple stimuli modulated FRET processes within thermoresponsive polymeric micelles. Angew Chem. 2010;122(30):5246–50.CrossRefGoogle Scholar
  63. 63.
    Algar WR, Krull UJ. Towards multi-colour strategies for the detection of oligonucleotide hybridization using quantum dots as energy donors in fluorescence resonance energy transfer (FRET). Anal Chim Acta. 2007;581(2):193–201.PubMedCrossRefGoogle Scholar
  64. 64.
    McKinney SA, Murphy CS, Hazelwood KL, Davidson MW, Looger LL. A bright and photostable photoconvertible fluorescent protein. Nat Methods. 2009;6(2):131–3.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Wiedenmann J, Ivanchenko S, Oswald F, Schmitt F, Röcker C, Salih A, et al. EosFP, a fluorescent marker protein with UV-inducible green-to-red fluorescence conversion. Proc Natl Acad Sci U S A. 2004;101(45):15905–10.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Hoi H, Shaner NC, Davidson MW, Cairo CW, Wang J, Campbell RE. A monomeric photoconvertible fluorescent protein for imaging of dynamic protein localization. J Mol Biol. 2010;401(5):776–91.PubMedCrossRefGoogle Scholar
  67. 67.
    Kuo C-P, Chuang C-N, Chang C-L, M-k L, Lian H-Y, Chia-Wen Wu K. White-light electrofluorescence switching from electrochemically convertible yellow and blue fluorescent conjugated polymers. J Mater Chem C. 2013;1(11):2121–30.CrossRefGoogle Scholar
  68. 68.
    Kwok SJJ, Choi M, Bhayana B, Zhang X, Ran C, Yun S-H. Two-photon excited photoconversion of cyanine-based dyes. Sci Rep. 2016;6:23866.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Maurel D, Banala S, Laroche T, Johnsson K. Photoactivatable and photoconvertible fluorescent probes for protein labeling. ACS Chem Biol. 2010;5(5):507–16.PubMedCrossRefGoogle Scholar
  70. 70.
    Liu S-H, Chang JT, Ng S-H, Chan S-C, Yen T-C. False positive fluorine-18 fluorodeoxy-D-glucose positron emission tomography finding caused by osteoradionecrosis in a nasopharyngeal carcinoma patient. Br J Radiol. 2004;77(915):257–60.PubMedCrossRefGoogle Scholar
  71. 71.
    Garg PK, Garg S, Zalutsky MR. Fluorine-18 labeling of monoclonal antibodies and fragments with preservation of immunoreactivity. Bioconjug Chem. 1991;2(1):44–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Lasne M-C, Perrio C, Rouden J, Barré L, Roeda D, Dolle F, et al. Chemistry of β +−emitting compounds based on fluorine-18. In: Krause W, editor. Contrast agents II: optical, ultrasound, X-ray and radiopharmaceutical imaging. Berlin: Springer; 2002. p. 201–58.CrossRefGoogle Scholar
  73. 73.
    Naswa N, Sharma P, Soundararajan R, Patnecha M, Lata S, Kumar R, et al. Preoperative characterization of indeterminate large adrenal masses with dual tracer PET-CT using fluorine-18 fluorodeoxyglucose and gallium-68-DOTANOC: initial results. Diagn Interv Radiol. 2013;19(4):294–8.PubMedGoogle Scholar
  74. 74.
    Guo W, Sun X, Jacobson O, Yan X, Min K, Srivatsan A, et al. Intrinsically radioactive [64Cu]CuInS/ZnS quantum dots for PET and optical imaging: improved radiochemical stability and controllable cerenkov luminescence. ACS Nano. 2015;9(1):488–95.PubMedCrossRefGoogle Scholar
  75. 75.
    Hirvonen J, Roivainen A, Virta J, Helin S, Någren K, Rinne JO. Human biodistribution and radiation dosimetry of 11C-(R)-PK11195, the prototypic PET ligand to image inflammation. Eur J Nucl Med Mol Imaging. 2010;37(3):606–12.PubMedCrossRefGoogle Scholar
  76. 76.
    Lee FT, O’Keefe GJ, Gan HK, Mountain AJ, Jones GR, Saunder TH, et al. Immuno-PET quantitation of de2-7 epidermal growth factor receptor expression in glioma using 124I-IMP-R4–labeled antibody ch806. J Nucl Med. 2010;51(6):967–72.PubMedCrossRefGoogle Scholar
  77. 77.
    Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, et al. Imaging brain amyloid in Alzheimer’s disease with Pittsburgh compound-B. Ann Neurol. 2004;55(3):306–19.PubMedCrossRefGoogle Scholar
  78. 78.
    Vassar PS, Culling CF. Fluorescent stains, with special reference to amyloid and connective tissues. Arch Pathol. 1959;68:487–98.PubMedGoogle Scholar
  79. 79.
    Conti M. Focus on time-of-flight PET: the benefits of improved time resolution. Eur J Nucl Med Mol Imaging. 2011;38(6):1147–57.PubMedCrossRefGoogle Scholar
  80. 80.
    Lois C, Jakoby BW, Long MJ, Hubner KF, Barker DW, Casey ME, et al. An assessment of the impact of incorporating time-of-flight information into clinical PET/CT imaging. J Nucl Med. 2010;51(2):237–45.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Stefan S, Gerben van der L, Herman TD, Dennis RS. First characterization of a digital SiPM based time-of-flight PET detector with 1 mm spatial resolution. Phys Med Biol. 2013;58(9):3061.CrossRefGoogle Scholar
  82. 82.
    Akamatsu G, Ishikawa K, Mitsumoto K, Taniguchi T, Ohya N, Baba S, et al. Improvement in PET/CT image quality with a combination of point-spread function and time-of-flight in relation to reconstruction parameters. J Nucl Med. 2012;53(11):1716–22.PubMedCrossRefGoogle Scholar
  83. 83.
    Berg E, Roncali E, Kapusta M, Du J, Cherry SR. A combined time-of-flight and depth-of-interaction detector for total-body positron emission tomography. Med Phys. 2016;43(2):939–50.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Choy G, O’Connor S, Diehn FE, Costouros N, Alexander HR, Choyke P, et al. Comparison of noninvasive fluorescent and bioluminescent small animal optical imaging. BioTechniques. 2003;35(5):1022–6. 8–30PubMedGoogle Scholar
  85. 85.
    Cool SK, Breyne K, Meyer E, De Smedt SC, Sanders NN. Comparison of in vivo optical systems for bioluminescence and fluorescence imaging. J Fluoresc. 2013;23(5):909–20.PubMedCrossRefGoogle Scholar
  86. 86.
    Moriyama EH, Niedre MJ, Jarvi MT, Mocanu JD, Moriyama Y, Subarsky P, et al. The influence of hypoxia on bioluminescence in luciferase-transfected gliosarcoma tumor cells in vitro. Photochem Photobiol Sci. 2008;7(6):675–80.PubMedCrossRefGoogle Scholar
  87. 87.
    Inoue Y, Sheng F, Kiryu S, Watanabe M, Ratanakanit H, Izawa K, et al. Gaussia luciferase for bioluminescence tumor monitoring in comparison with firefly luciferase. Mol Imaging. 2011;10(5):377–85.PubMedGoogle Scholar
  88. 88.
    Song H-T, Jordan EK, Lewis BK, Liu W, Ganjei J, Klaunberg B, et al. Rat model of metastatic breast cancer monitored by MRI at 3 tesla and bioluminescence imaging with histological correlation. J Transl Med. 2009;7(1):88.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Song H-T, Lewis BK, Liu W, Jordan EK, Klaunberg B, Despress D, et al. Quantitative measurement of cerebral metastatic tumor burden of breast cancer cells in a nude rat model using T2* map histograms with bioluminescence imaging correlation. Joint annual meeting ISMRM-ESMRMB; 19–25 May; Berlin 2007.Google Scholar
  90. 90.
    Kim J-B, Urban K, Cochran E, Lee S, Ang A, Rice B, et al. Non-invasive detection of a small number of bioluminescent cancer cells in vivo. PLoS One. 2010;5(2):e9364.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Sinn PL, Arias AC, Brogden KA, McCray PB. Lentivirus vector can be readministered to nasal epithelia without blocking immune responses. J Virol. 2008;82(21):10684–92.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Thomas AM, Palma JL, Shea LD. Sponge-mediated lentivirus delivery to acute and chronic spinal cord injuries. J Control Release. 2015;204:1–10.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Toelen J, Deroose CM, Gijsbers R, Reumers V, Sbragia LN, Vets S, et al. Fetal gene transfer with lentiviral vectors: long-term in vivo follow-up evaluation in a rat model. Am J Obstet Gynecol. 2007;196(4):352.e1–6.CrossRefGoogle Scholar
  94. 94.
    Maguire CA, Bovenberg MS, Crommentuijn MHW, Niers JM, Kerami M, Teng J, et al. Triple bioluminescence imaging for in vivo monitoring of cellular processes. Mol Ther Nucleic Acids. 2013;2:e99.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Weiss MS, Peñalver Bernabé B, Bellis AD, Broadbelt LJ, Jeruss JS, Shea LD. Dynamic, large-scale profiling of transcription factor activity from live cells in 3D culture. PLoS One. 2010;5(11):e14026.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Hoyler T, Klose Christoph SN, Souabni A, Turqueti-Neves A, Pfeifer D, Rawlins Emma L, et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity. 2012;37(4):634–48.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Low RN, Barone RM. Combined diffusion-weighted and gadolinium-enhanced MRI can accurately predict the peritoneal cancer index preoperatively in patients being considered for cytoreductive surgical procedures. Ann Surg Oncol. 2012;19(5):1394–401.PubMedCrossRefGoogle Scholar
  98. 98.
    Larose E, Kinlay S, Selwyn AP, Yeghiazarians Y, Yucel EK, Kacher DF, et al. Improved characterization of atherosclerotic plaques by gadolinium contrast during intravascular magnetic resonance imaging of human arteries. Atherosclerosis. 2008;196(2):919–25.PubMedCrossRefGoogle Scholar
  99. 99.
    Berman SM, Walczak P, Bulte JW. MRI of transplanted neural stem cells. Methods Mol Biol. 2011;711:435–49.PubMedCrossRefGoogle Scholar
  100. 100.
    Broome DR. Nephrogenic systemic fibrosis associated with gadolinium based contrast agents: a summary of the medical literature reporting. Eur J Radiol. 2008;66(2):230–4.PubMedCrossRefGoogle Scholar
  101. 101.
    Flood TF, Stence NV, Maloney JA, Mirsky DM. Pediatric brain: repeated exposure to linear gadolinium-based contrast material is associated with increased signal intensity at unenhanced T1-weighted MR imaging. Radiology. 2017;282:222–8.PubMedCrossRefGoogle Scholar
  102. 102.
    McDonald RJ, McDonald JS, Kallmes DF, Jentoft ME, Murray DL, Thielen KR, et al. Intracranial gadolinium deposition after contrast-enhanced MR imaging. Radiology. 2015;275(3):772–82.PubMedCrossRefGoogle Scholar
  103. 103.
    Kim T, Momin E, Choi J, Yuan K, Zaidi H, Kim J, et al. Mesoporous silica-coated hollow manganese oxide nanoparticles as positive T1 contrast agents for labeling and MRI tracking of adipose-derived mesenchymal stem cells. J Am Chem Soc. 2011;133(9):2955–61.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Gilad AA, Walczak P, McMahon MT, Na HB, Lee JH, An K, et al. MR tracking of transplanted cells with “positive contrast” using manganese oxide nanoparticles. Magn Reson Med. 2008;60(1):1–7.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Bulte JW, Kraitchman DL. Monitoring cell therapy using iron oxide MR contrast agents. Curr Pharm Biotechnol. 2004;5(6):567–84.PubMedCrossRefGoogle Scholar
  106. 106.
    Tang Y, Zhang C, Wang J, Lin X, Zhang L, Yang Y, et al. MRI/SPECT/fluorescent tri-modal probe for evaluating the homing and therapeutic efficacy of transplanted mesenchymal stem cells in a rat ischemic stroke model. Adv Funct Mater. 2015;25(7):1024–34.PubMedCrossRefGoogle Scholar
  107. 107.
    Bulte JW. Hot spot MRI emerges from the background. Nat Biotechnol. 2005;23(8):945–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Ruiz-Cabello J, Walczak P, Kedziorek DA, Chacko VP, Schmieder AH, Wickline SA, et al. In vivo “hot spot” MR imaging of neural stem cells using fluorinated nanoparticles. Magn Reson Med. 2008;60(6):1506–11.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Srinivas M, Morel PA, Ernst LA, Laidlaw DH, Ahrens ET. Fluorine-19 MRI for visualization and quantification of cell migration in a diabetes model. Magn Reson Med. 2007;58(4):725–34.PubMedCrossRefGoogle Scholar
  110. 110.
    Flögel U, Ding Z, Hardung H, Jander S, Reichmann G, Jacoby C, et al. In vivo monitoring of inflammation after Cardiac and cerebral ischemia by fluorine magnetic resonance imaging. Circulation. 2008;118(2):140–8.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Ahrens ET, Flores R, Xu H, Morel PA. In vivo imaging platform for tracking immunotherapeutic cells. Nat Biotechnol. 2005;23(8):983–7.PubMedCrossRefGoogle Scholar
  112. 112.
    Bar-Shir A, Yadav NN, Gilad AA, van Zijl PC, McMahon MT, Bulte JW. Single (19)F probe for simultaneous detection of multiple metal ions using miCEST MRI. J Am Chem Soc. 2015;137(1):78–81.PubMedCrossRefGoogle Scholar
  113. 113.
    van Zijl PC, Yadav NN. Chemical exchange saturation transfer (CEST): what is in a name and what isn’t? Magn Reson Med. 2011;65(4):927–48.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Davis KA, Nanga RPR, Das S, Chen SH, Hadar PN, Pollard JR, et al. Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy. Sci Transl Med. 2015;7(309):309ra161.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Cai K, Singh A, Poptani H, Li W, Yang S, Lu Y, et al. CEST signal at 2 ppm (CEST@2ppm) from Z-spectral fitting correlates with creatine distribution in brain tumor. NMR Biomed. 2015;28(1):1–8.PubMedGoogle Scholar
  116. 116.
    Longo DL, Busato A, Lanzardo S, Antico F, Aime S. Imaging the pH evolution of an acute kidney injury model by means of iopamidol, a MRI-CEST pH-responsive contrast agent. Magn Reson Med. 2013;70(3):859–64.PubMedCrossRefGoogle Scholar
  117. 117.
    Chan KWY, Liu G, Song X, Kim H, Yu T, Arifin DR, et al. MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted-cell viability. Nat Mater. 2013;12(3):268–75.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Delli Castelli D, Terreno E, Aime S. YbIII-HPDO3A: a dual pH- and temperature-responsive CEST agent. Angew Chem Int Ed. 2011;50(8):1798–800.CrossRefGoogle Scholar
  119. 119.
    Liu G, Moake M, Y-e H-e, Long CM, Chan KWY, Cardona A, et al. In vivo multicolor molecular MR imaging using diamagnetic chemical exchange saturation transfer liposomes. Magn Reson Med. 2012;67(4):1106–13.PubMedCrossRefGoogle Scholar
  120. 120.
    Ngen EJ, Bar-Shir A, Jablonska A, Liu G, Song X, Ansari R, et al. Imaging the DNA alkylator melphalan by CEST MRI: an advanced approach to theranostics. Mol Pharm. 2016;13(9):3043–53.PubMedCrossRefGoogle Scholar
  121. 121.
    Liu H, Jablonska A, Li Y, Cao S, Liu D, Chen H, et al. Label-free CEST MRI detection of citicoline-liposome drug delivery in ischemic stroke. Theranostics. 2016;6(10):1588–600.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Sour A, Jenni S, Ortí-Suárez A, Schmitt J, Heitz V, Bolze F, et al. Four gadolinium(III) complexes appended to a porphyrin: a water-soluble molecular Theranostic agent with remarkable relaxivity suited for MRI tracking of the photosensitizer. Inorg Chem. 2016;55(9):4545–54.PubMedCrossRefGoogle Scholar
  123. 123.
    Cutrin JC, Crich SG, Burghelea D, Dastrù W, Aime S. Curcumin/Gd loaded apoferritin: a novel “Theranostic” agent to prevent hepatocellular damage in toxic induced acute hepatitis. Mol Pharm. 2013;10(5):2079–85.PubMedCrossRefGoogle Scholar
  124. 124.
    Liu Q, Zhu H, Qin J, Dong H, Du J. Theranostic vesicles based on bovine serum albumin and poly(ethylene glycol)-block-poly(l-lactic-co-glycolic acid) for magnetic resonance imaging and anticancer drug delivery. Biomacromolecules. 2014;15(5):1586–92.PubMedCrossRefGoogle Scholar
  125. 125.
    Yu T, Chan KWY, Anonuevo A, Song X, Schuster BS, Chattopadhyay S, et al. Liposome-based mucus-penetrating particles (MPP) for mucosal theranostics: demonstration of diamagnetic chemical exchange saturation transfer (diaCEST) magnetic resonance imaging (MRI). Nanomedicine. 2015;11(2):401–5.PubMedCrossRefGoogle Scholar
  126. 126.
    Gerloff C, Bushara K, Sailer A, Wassermann EM, Chen R, Matsuoka T, et al. Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke. Brain. 2006;129(3):791–808.PubMedCrossRefGoogle Scholar
  127. 127.
    Moore A, Medarova Z, Potthast A, Dai G. In vivo targeting of underglycosylated MUC-1 tumor antigen using a multimodal imaging probe. Cancer Res. 2004;64(5):1821–7.PubMedCrossRefGoogle Scholar
  128. 128.
    Nahrendorf M, Keliher E, Marinelli B, Waterman P, Feruglio PF, Fexon L, et al. Hybrid PET-optical imaging using targeted probes. Proc Natl Acad Sci. 2010;107(17):7910–5.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Rieter WJ, Kim JS, Taylor KML, An H, Lin W, Tarrant T, et al. Hybrid silica nanoparticles for multimodal imaging. Angew Chem Int Ed. 2007;46(20):3680–2.CrossRefGoogle Scholar
  130. 130.
    Levin C, Glover G, Deller T, McDaniel D, Peterson W, Maramraju SH. Prototype time-of-flight PET ring integrated with a 3T MRI system for simultaneous whole-body PET/MR imaging. J Nucl Med. 2013;54(Suppl 2):148.Google Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Russell H. Morgan Department of Radiology and Radiological ScienceJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations