Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Clinical imaging in regenerative medicine

Nature Biotechnology volume 32, pages 804–818 (2014)Cite this article

Subjects

Abstract

In regenerative medicine, clinical imaging is indispensable for characterizing damaged tissue and for measuring the safety and efficacy of therapy. However, the ability to track the fate and function of transplanted cells with current technologies is limited. Exogenous contrast labels such as nanoparticles give a strong signal in the short term but are unreliable long term. Genetically encoded labels are good both short- and long-term in animals, but in the human setting they raise regulatory issues related to the safety of genomic integration and potential immunogenicity of reporter proteins. Imaging studies in brain, heart and islets share a common set of challenges, including developing novel labeling approaches to improve detection thresholds and early delineation of toxicity and function. Key areas for future research include addressing safety concerns associated with genetic labels and developing methods to follow cell survival, differentiation and integration with host tissue. Imaging may bridge the gap between cell therapies and health outcomes by elucidating mechanisms of action through longitudinal monitoring.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The human body contains ∼3.7 × 1013 cells10.

Katie Vicari/Nature Publishing Group

Figure 2: Tracking cell fate by noninvasive imaging requires either direct or indirect labeling.

Katie Vicari/Nature Publishing Group

Figure 3: Examples of clinical imaging used to identify and track labeled cells in the body.

Similar content being viewed by others

References

  1. Daar, A.S. & Greenwood, H.L. A proposed definition of regenerative medicine. J. Tissue Eng. Regen. Med. 1, 179–184 (2007).

    CAS  PubMed  Google Scholar 

  2. Robey, T.E., Saiget, M.K., Reinecke, H. & Murry, C.E. Systems approaches to preventing transplanted cell death in cardiac repair. J. Mol. Cell. Cardiol. 45, 567–581 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. de Almeida, P.E., van Rappard, J.R. & Wu, J.C. In vivo bioluminescence for tracking cell fate and function. Am. J. Physiol. Heart Circ. Physiol. 301, H663–H671 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Nguyen, P.K., Riegler, J. & Wu, J.C. Stem cell imaging: from bench to bedside. Cell Stem Cell 14, 431–444 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Roura, S., Galvez-Monton, C. & Bayes-Genis, A. Bioluminescence imaging: a shining future for cardiac regeneration. J. Cell. Mol. Med. 17, 693–703 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Progatzky, F., Dallman, M.J. & Lo Celso, C. From seeing to believing: labelling strategies for in vivo cell-tracking experiments. Interface Focus 3 20130001 (2013).

    PubMed  PubMed Central  Google Scholar 

  7. Weigert, R., Porat-Shliom, N. & Amornphimoltham, P. Imaging cell biology in live animals: ready for prime time. J. Cell Biol. 201, 969–979 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Gu, E., Chen, W.Y., Gu, J., Burridge, P. & Wu, J.C. Molecular imaging of stem cells: tracking survival, biodistribution, tumorigenicity, and immunogenicity. Theranostics 2, 335–345 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Wagers, A.J. The stem cell niche in regenerative medicine. Cell Stem Cell 10, 362–369 (2012).

    CAS  PubMed  Google Scholar 

  10. Bianconi, E. et al. An estimation of the number of cells in the human body. Ann. Hum. Biol. 40, 463–471 (2013).

    PubMed  Google Scholar 

  11. Fischer, U.M. et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 18, 683–692 (2009).

    CAS  PubMed  Google Scholar 

  12. Harting, M.T. et al. Intravenous mesenchymal stem cell therapy for traumatic brain injury. J. Neurosurg. 110, 1189–1197 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Everaert, B.R. et al. Multimodal in vivo imaging reveals limited allograft survival, intrapulmonary cell trapping and minimal evidence for ischemia-directed BMSC homing. BMC Biotechnol. 12, 93 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ramsden, C.M. et al. Stem cells in retinal regeneration: past, present and future. Development 140, 2576–2585 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Olivetti, G., Capasso, J.M., Sonnenblick, E.H. & Anversa, P. Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ. Res. 67, 23–34 (1990).

    CAS  PubMed  Google Scholar 

  16. Husser, O. et al. Head-to-head comparison of 1 week versus 6 months CMR-derived infarct size for prediction of late events after STEMI. Int. J. Cardiovasc. Imaging 29, 1499–1509 (2013).

    PubMed  Google Scholar 

  17. McCall, M. & Shapiro, A.M. Update on islet transplantation. Interface Focus. 3, 20130001 (2012).

    Google Scholar 

  18. Moszczynska, A. et al. Why is parkinsonism not a feature of human methamphetamine users? Brain 127, 363–370 (2004).

    PubMed  Google Scholar 

  19. Kordower, J.H. et al. Fetal nigral grafts survive and mediate clinical benefit in a patient with Parkinson's disease. Mov. Disord. 13, 383–393 (1998).

    CAS  PubMed  Google Scholar 

  20. Everall, I., Barnes, H., Spargo, E. & Lantos, P. Assessment of neuronal density in the putamen in human immunodeficiency virus (HIV) infection. Application of stereology and spatial analysis of quadrats. J. Neurovirol. 1, 126–129 (1995).

    CAS  PubMed  Google Scholar 

  21. Kumar, R. et al. Global and regional putamen volume loss in patients with heart failure. Eur. J. Heart Fail. 13, 651–655 (2011).

    PubMed  PubMed Central  Google Scholar 

  22. Ahrens, E.T. & Bulte, J.W. Tracking immune cells in vivo using magnetic resonance imaging. Nat. Rev. Immunol. 13, 755–763 (2013).

    CAS  PubMed  Google Scholar 

  23. Shapiro, E.M., Sharer, K., Skrtic, S. & Koretsky, A.P. In vivo detection of single cells by MRI. Magn. Reson. Med. 55, 242–249 (2006).

    PubMed  Google Scholar 

  24. Shapiro, E.M. et al. MRI detection of single particles for cellular imaging. Proc. Natl. Acad. Sci. USA 101, 10901–10906 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ahrens, E.T. & Zhong, J. In vivo MRI cell tracking using perfluorocarbon probes and fluorine-19 detection. NMR Biomed. 26, 860–871 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Arbab, A.S. & Frank, J.A. Cellular MRI and its role in stem cell therapy. Regen. Med. 3, 199–215 (2008).

    CAS  PubMed  Google Scholar 

  27. Nguyen, P.K., Lan, F., Wang, Y. & Wu, J.C. Imaging: guiding the clinical translation of cardiac stem cell therapy. Circ. Res. 109, 962–979 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Dahnke, H. & Schaeffter, T. Limits of detection of SPIO at 3.0 T using T2 relaxometry. Magn. Reson. Med. 53, 1202–1206 (2005).

    CAS  PubMed  Google Scholar 

  29. Rueger, M.A. & Androutsellis-Theotokis, A. Identifying endogenous neural stem cells in the adult brain in vitro and in vivo: novel approaches. Curr. Pharm. Des. 19, 6499–6506 (2013).

    CAS  PubMed  Google Scholar 

  30. Arbab, A.S. et al. In vivo cellular imaging for translational medical research. Curr. Med. Imaging Rev. 5, 19–38 (2009).

    PubMed  PubMed Central  Google Scholar 

  31. Bar-Shir, A. et al. Human Protamine-1 as an MRI reporter gene based on chemical exchange. ACS Chem. Biol. 9, 134–138 (2013).

    PubMed  PubMed Central  Google Scholar 

  32. Willmann, J.K. et al. Imaging gene expression in human mesenchymal stem cells: from small to large animals. Radiology 252, 117–127 (2009).

    PubMed  PubMed Central  Google Scholar 

  33. Arbab, A.S., Liu, W. & Frank, J.A. Cellular magnetic resonance imaging: current status and future prospects. Expert Rev. Med. Devices 3, 427–439 (2006).

    CAS  PubMed  Google Scholar 

  34. Amsalem, Y. et al. Iron-oxide labeling and outcome of transplanted mesenchymal stem cells in the infarcted myocardium. Circulation 116, I38–I45 (2007).

    CAS  PubMed  Google Scholar 

  35. de Vries, I.J. et al. Magnetic resonance tracking of dendritic cells in melanoma patients for monitoring of cellular therapy. Nat. Biotechnol. 23, 1407–1413 (2005).

    CAS  PubMed  Google Scholar 

  36. Partlow, K.C. et al. 19F magnetic resonance imaging for stem/progenitor cell tracking with multiple unique perfluorocarbon nanobeacons. FASEB J. 21, 1647–1654 (2007).

    CAS  PubMed  Google Scholar 

  37. Zhen, Z. & Xie, J. Development of manganese-based nanoparticles as contrast probes for magnetic resonance imaging. Theranostics 2, 45–54 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bara, C. et al. In vivo echocardiographic imaging of transplanted human adult stem cells in the myocardium labeled with clinically applicable CliniMACS nanoparticles. J. Am. Soc. Echocardiogr. 19, 563–568 (2006).

    PubMed  Google Scholar 

  39. Bulte, J.W. In vivo MRI cell tracking: clinical studies. AJR Am. J. Roentgenol. 193, 314–325 (2009).

    PubMed  PubMed Central  Google Scholar 

  40. Zhu, J., Zhou, L. & Wu, F.X. Tracking neural stem cells in patients with brain trauma. N. Engl. J. Med. 355, 2376–2378 (2006).

    CAS  PubMed  Google Scholar 

  41. Laskey, W.K., Feinendegen, L.E., Neumann, R.D. & Dilsizian, V. Low-level ionizing radiation from noninvasive cardiac imaging: can we extrapolate estimated risks from epidemiologic data to the clinical setting? JACC Cardiovasc. Imaging 3, 517–524 (2010).

    PubMed  Google Scholar 

  42. Brenner, W. et al. 111In-labeled CD34+ hematopoietic progenitor cells in a rat myocardial infarction model. J. Nucl. Med. 45, 512–518 (2004).

    CAS  PubMed  Google Scholar 

  43. Wolfs, E. et al. 18F-FDG labeling of mesenchymal stem cells and multipotent adult progenitor cells for PET imaging: effects on ultrastructure and differentiation capacity. J. Nucl. Med. 54, 447–454 (2013).

    CAS  PubMed  Google Scholar 

  44. Wu, C. et al. In vivo cell tracking via (1)(8)F-fluorodeoxyglucose labeling: a review of the preclinical and clinical applications in cell-based diagnosis and therapy. Clin. Imaging 37, 28–36 (2013).

    PubMed  Google Scholar 

  45. Terrovitis, J. et al. Magnetic resonance imaging overestimates ferumoxide-labeled stem cell survival after transplantation in the heart. Circulation 117, 1555–1562 (2008).

    PubMed  Google Scholar 

  46. Naumova, A.V. et al. Magnetic resonance imaging tracking of graft survival in the infarcted heart: iron oxide particles versus ferritin overexpression approach. J. Cardiovasc. Pharmacol. Ther. 19, 358–367 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Pawelczyk, E. et al. In vitro model of bromodeoxyuridine or iron oxide nanoparticle uptake by activated macrophages from labeled stem cells: implications for cellular therapy. Stem Cells 26, 1366–1375 (2008).

    CAS  PubMed  Google Scholar 

  48. Pawelczyk, E. et al. In vivo transfer of intracellular labels from locally implanted bone marrow stromal cells to resident tissue macrophages. PLoS ONE 4, e6712 (2009).

    PubMed  PubMed Central  Google Scholar 

  49. Walczak, P., Kedziorek, D.A., Gilad, A.A., Barnett, B.P. & Bulte, J.W. Applicability and limitations of MR tracking of neural stem cells with asymmetric cell division and rapid turnover: the case of the shiverer dysmyelinated mouse brain. Magn. Reson. Med. 58, 261–269 (2007).

    CAS  PubMed  Google Scholar 

  50. Arbab, A.S. et al. Characterization of biophysical and metabolic properties of cells labeled with superparamagnetic iron oxide nanoparticles and transfection agent for cellular MR imaging. Radiology 229, 838–846 (2003).

    PubMed  Google Scholar 

  51. Thu, M.S. et al. Self-assembling nanocomplexes by combining ferumoxytol, heparin and protamine for cell tracking by magnetic resonance imaging. Nat. Med. 18, 463–467 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Rigol, M. et al. Hemosiderin deposits confounds tracking of iron-oxide-labeled stem cells: an experimental study. Transplant. Proc. 40, 3619–3622 (2008).

    CAS  PubMed  Google Scholar 

  53. Schäfer, R. et al. Labeling of human mesenchymal stromal cells with superparamagnetic iron oxide leads to a decrease in migration capacity and colony formation ability. Cytotherapy 11, 68–78 (2009).

    PubMed  Google Scholar 

  54. Kostura, L., Kraitchman, D.L., Mackay, A.M., Pittenger, M.F. & Bulte, J.W. Feridex labeling of mesenchymal stem cells inhibits chondrogenesis but not adipogenesis or osteogenesis. NMR Biomed. 17, 513–517 (2004).

    PubMed  Google Scholar 

  55. Arbab, A.S. et al. Labeling of cells with ferumoxides-protamine sulfate complexes does not inhibit function or differentiation capacity of hematopoietic or mesenchymal stem cells. NMR Biomed. 18, 553–559 (2005).

    CAS  PubMed  Google Scholar 

  56. Campan, M. et al. Ferritin as a reporter gene for in vivo tracking of stem cells by 1.5-T cardiac MRI in a rat model of myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 300, H2238–H2250 (2011).

    CAS  PubMed  Google Scholar 

  57. Naumova, A.V. et al. Ferritin overexpression for noninvasive magnetic resonance imaging-based tracking of stem cells transplanted into the heart. Mol. Imaging 9, 201–210 (2010).

    CAS  PubMed  Google Scholar 

  58. Naumova, A.V. et al. Quantification of MRI signal of transgenic grafts overexpressing ferritin in murine myocardial infarcts. NMR Biomed. 25, 1187–1195 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Gyöngyösi, M. et al. Serial noninvasive in vivo positron emission tomographic tracking of percutaneously intramyocardially injected autologous porcine mesenchymal stem cells modified for transgene reporter gene expression. Circ. Cardiovasc. Imaging 1, 94–103 (2008).

    PubMed  PubMed Central  Google Scholar 

  60. Yaghoubi, S.S. et al. Noninvasive detection of therapeutic cytolytic T cells with 18F-FHBG PET in a patient with glioma. Nat. Clin. Pract. Oncol. 6, 53–58 (2009).

    CAS  PubMed  Google Scholar 

  61. Zhang, Y. et al. Tracking stem cell therapy in the myocardium: applications of positron emission tomography. Curr. Pharm. Des. 14, 3835–3853 (2008).

    CAS  PubMed  Google Scholar 

  62. Yaghoubi, S.S., Campbell, D.O., Radu, C.G. & Czernin, J. Positron emission tomography reporter genes and reporter probes: gene and cell therapy applications. Theranostics 2, 374–391 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Tannous, B.A. et al. Metabolic biotinylation of cell surface receptors for in vivo imaging. Nat. Methods 3, 391–396 (2006).

    CAS  PubMed  Google Scholar 

  64. So, P.W. et al. Efficient and rapid labeling of transplanted cell populations with superparamagnetic iron oxide nanoparticles using cell surface chemical biotinylation for in vivo monitoring by MRI. Cell Transplant. 19, 419–429 (2010).

    PubMed  Google Scholar 

  65. Ward, K.M., Aletras, A.H. & Balaban, R.S. A new class of contrast agents for MRI based on proton chemical exchange dependent saturation transfer (CEST). J. Magn. Reson. 143, 79–87 (2000).

    CAS  PubMed  Google Scholar 

  66. van Zijl, P.C. & Yadav, N.N. Chemical exchange saturation transfer (CEST): what is in a name and what isn't? Magn. Reson. Med. 65, 927–948 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhou, J., Payen, J.F., Wilson, D.A., Traystman, R.J. & van Zijl, P.C. Using the amide proton signals of intracellular proteins and peptides to detect pH effects in MRI. Nat. Med. 9, 1085–1090 (2003).

    CAS  PubMed  Google Scholar 

  68. Chan, K.W. et al. MRI-detectable pH nanosensors incorporated into hydrogels for in vivo sensing of transplanted-cell viability. Nat. Mater. 12, 268–275 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Zhou, J. et al. Three-dimensional amide proton transfer MR imaging of gliomas: Initial experience and comparison with gadolinium enhancement. J. Magn. Reson. Imaging 38, 1119–1128 (2013).

    PubMed  Google Scholar 

  70. Bar-Shir, A., Liu, G., Greenberg, M.M., Bulte, J.W. & Gilad, A.A. Synthesis of a probe for monitoring HSV1-tk reporter gene expression using chemical exchange saturation transfer MRI. Nat. Protoc. 8, 2380–2391 (2013).

    CAS  PubMed  Google Scholar 

  71. Berger, C., Flowers, M.E., Warren, E.H. & Riddell, S.R. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK-modified donor T cells after allogeneic hematopoietic cell transplantation. Blood 107, 2294–2302 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Seggewiss, R. et al. Acute myeloid leukemia is associated with retroviral gene transfer to hematopoietic progenitor cells in a rhesus macaque. Blood 107, 3865–3867 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Vrtovec, B. et al. Comparison of transendocardial and intracoronary CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Circulation 128, S42–S49 (2013).

    CAS  PubMed  Google Scholar 

  74. Qiao, H. et al. Death and proliferation time course of stem cells transplanted in the myocardium. Mol. Imaging Biol. 11, 408–414 (2009).

    PubMed  PubMed Central  Google Scholar 

  75. Perin, E.C. et al. Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model. PLoS ONE 6, e22949 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Mendez, I. et al. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson's disease. Brain 128, 1498–1510 (2005).

    PubMed  Google Scholar 

  77. Sosnovik, D.E. et al. Microstructural impact of ischemia and bone marrow-derived cell therapy revealed with diffusion tensor magnetic resonance imaging tractography of the heart in vivo. Circulation 129, 1731–1741 (2014).

    PubMed  PubMed Central  Google Scholar 

  78. Kang, W.J. et al. Tissue distribution of 18F-FDG-labeled peripheral hematopoietic stem cells after intracoronary administration in patients with myocardial infarction. J. Nucl. Med. 47, 1295–1301 (2006).

    PubMed  Google Scholar 

  79. Schächinger, V. et al. Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium. Circulation 118, 1425–1432 (2008).

    PubMed  Google Scholar 

  80. Vrtovec, B. et al. Effects of intracoronary CD34+ stem cell transplantation in nonischemic dilated cardiomyopathy patients: 5-year follow-up. Circ. Res. 112, 165–173 (2013).

    CAS  PubMed  Google Scholar 

  81. Elhami, E. et al. Assessment of three techniques for delivering stem cells to the heart using PET and MR imaging. EJNMMI Research 3, 72 (2013).

    PubMed  PubMed Central  Google Scholar 

  82. van der Bogt, K.E. et al. Comparison of different adult stem cell types for treatment of myocardial ischemia. Circulation 118, S121–S129 (2008).

    PubMed  PubMed Central  Google Scholar 

  83. Templin, C. et al. Transplantation and tracking of human-induced pluripotent stem cells in a pig model of myocardial infarction: assessment of cell survival, engraftment, and distribution by hybrid single photon emission computed tomography/computed tomography of sodium iodide symporter transgene expression. Circulation 126, 430–439 (2012).

    CAS  PubMed  Google Scholar 

  84. Malliaras, K. et al. Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction). J. Am. Coll. Cardiol. 63, 110–122 (2014).

    PubMed  Google Scholar 

  85. Makkar, R.R. et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet 379, 895–904 (2012).

    PubMed  PubMed Central  Google Scholar 

  86. Chugh, A.R. et al. Administration of cardiac stem cells in patients with ischemic cardiomyopathy: the SCIPIO trial: surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation 126, S54–S64 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. McGill, L.A. et al. Reproducibility of in-vivo diffusion tensor cardiovascular magnetic resonance in hypertrophic cardiomyopathy. J. Cardiovasc. Magn. Reson. 14, 86 (2012).

    PubMed  PubMed Central  Google Scholar 

  88. Mekkaoui, C. et al. Fiber architecture in remodeled myocardium revealed with a quantitative diffusion CMR tractography framework and histological validation. J. Cardiovasc. Magn. Reson. 14, 70 (2012).

    PubMed  PubMed Central  Google Scholar 

  89. Laflamme, M.A. et al. Cardiomyocytes derived from human embryonic stem cells in pro-survival factors enhance function of infarcted rat hearts. Nat. Biotechnol. 25, 1015–1024 (2007).

    CAS  PubMed  Google Scholar 

  90. Shiba, Y. et al. Human ES-cell-derived cardiomyocytes electrically couple and suppress arrhythmias in injured hearts. Nature 489, 322–325 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Chong, J.J. et al. Human embryonic-stem-cell-derived cardiomyocytes regenerate non-human primate hearts. Nature 510, 273–277 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Gepts, W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14, 619–633 (1965).

    CAS  PubMed  Google Scholar 

  93. Reaven, G.M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 37, 1595–1607 (1988).

    CAS  PubMed  Google Scholar 

  94. Shapiro, A.M. et al. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343, 230–238 (2000).

    CAS  PubMed  Google Scholar 

  95. Ryan, E.A. et al. Five-year follow-up after clinical islet transplantation. Diabetes 54, 2060–2069 (2005).

    CAS  PubMed  Google Scholar 

  96. Barshes, N.R., Wyllie, S. & Goss, J.A. Inflammation-mediated dysfunction and apoptosis in pancreatic islet transplantation: implications for intrahepatic grafts. J. Leukoc. Biol. 77, 587–597 (2005).

    CAS  PubMed  Google Scholar 

  97. Matveyenko, A.V. & Butler, P.C. Relationship between beta-cell mass and diabetes onset. Diabetes Obes. Metab. 10 (suppl. 4), 23–31 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Rother, K.I. & Harlan, D.M. Challenges facing islet transplantation for the treatment of type 1 diabetes mellitus. J. Clin. Invest. 114, 877–883 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Kroon, E. et al. Pancreatic endoderm derived from human embryonic stem cells generates glucose-responsive insulin-secreting cells in vivo. Nat. Biotechnol. 26, 443–452 (2008).

    CAS  PubMed  Google Scholar 

  100. Rezania, A. et al. Maturation of human embryonic stem cell-derived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 61, 2016–2029 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Blum, B. et al. Functional beta-cell maturation is marked by an increased glucose threshold and by expression of urocortin 3. Nat. Biotechnol. 30, 261–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Van Hoof, D. & Liku, M.E. Directed differentiation of human pluripotent stem cells along the pancreatic endocrine lineage. Methods Mol. Biol. 997, 127–140 (2013).

    CAS  PubMed  Google Scholar 

  103. Toso, C. et al. Clinical magnetic resonance imaging of pancreatic islet grafts after iron nanoparticle labeling. Am. J. Transplant. 8, 701–706 (2008).

    CAS  PubMed  Google Scholar 

  104. Saudek, F. et al. Magnetic resonance imaging of pancreatic islets transplanted into the liver in humans. Transplantation 90, 1602–1606 (2010).

    PubMed  Google Scholar 

  105. Eich, T., Eriksson, O. & Lundgren, T. Visualization of early engraftment in clinical islet transplantation by positron-emission tomography. N. Engl. J. Med. 356, 2754–2755 (2007).

    CAS  PubMed  Google Scholar 

  106. Eriksson, O. et al. Positron emission tomography in clinical islet transplantation. Am. J. Transplant. 9, 2816–2824 (2009).

    CAS  PubMed  Google Scholar 

  107. Evgenov, N.V. et al. In vivo imaging of immune rejection in transplanted pancreatic islets. Diabetes 55, 2419–2428 (2006).

    CAS  PubMed  Google Scholar 

  108. Evgenov, N.V., Medarova, Z., Dai, G., Bonner-Weir, S. & Moore, A. In vivo imaging of islet transplantation. Nat. Med. 12, 144–148 (2006).

    CAS  PubMed  Google Scholar 

  109. Tai, J.H. et al. Imaging islets labeled with magnetic nanoparticles at 1.5 Tesla. Diabetes 55, 2931–2938 (2006).

    CAS  PubMed  Google Scholar 

  110. Hellman, B. Actual distribution of the number and volume of the islets of Langerhans in different size classes in non-diabetic humans of varying ages. Nature 184 (suppl. 19), 1498–1499 (1959).

    PubMed  Google Scholar 

  111. Medarova, Z., Evgenov, N.V., Dai, G., Bonner-Weir, S. & Moore, A. In vivo multimodal imaging of transplanted pancreatic islets. Nat. Protoc. 1, 429–435 (2006).

    CAS  PubMed  Google Scholar 

  112. Crowe, L.A. et al. A novel method for quantitative monitoring of transplanted islets of langerhans by positive contrast magnetic resonance imaging. Am. J. Transplant. 11, 1158–1168 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Grobner, T. Gadolinium–a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol. Dial. Transplant. 21, 1104–1108 (2006).

    CAS  PubMed  Google Scholar 

  114. Arifin, D.R. et al. Trimodal gadolinium-gold microcapsules containing pancreatic islet cells restore normoglycemia in diabetic mice and can be tracked by using US, CT, and positive-contrast MR imaging. Radiology 260, 790–798 (2011).

    PubMed  PubMed Central  Google Scholar 

  115. Srinivas, M. et al. Imaging of cellular therapies. Adv. Drug Deliv. Rev. 62, 1080–1093 (2010).

    CAS  PubMed  Google Scholar 

  116. Bonetto, F. et al. A novel (19)F agent for detection and quantification of human dendritic cells using magnetic resonance imaging. Int. J. Cancer 129, 365–373 (2011).

    CAS  PubMed  Google Scholar 

  117. Bonetto, F. et al. A large-scale (19) F MRI-based cell migration assay to optimize cell therapy. NMR Biomed. 25, 1095–1103 (2012).

    CAS  PubMed  Google Scholar 

  118. Barnett, B.P. et al. Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging. Radiology 258, 182–191 (2011).

    PubMed  PubMed Central  Google Scholar 

  119. Barnett, B.P. et al. Use of perfluorocarbon nanoparticles for non-invasive multimodal cell tracking of human pancreatic islets. Contrast Media Mol. Imaging 6, 251–259 (2011).

    CAS  PubMed  Google Scholar 

  120. Barnett, B.P. et al. Magnetic resonance-guided, real-time targeted delivery and imaging of magnetocapsules immunoprotecting pancreatic islet cells. Nat. Med. 13, 986–991 (2007).

    CAS  PubMed  Google Scholar 

  121. Lubag, A.J., De Leon-Rodriguez, L.M., Burgess, S.C. & Sherry, A.D. Noninvasive MRI of beta-cell function using a Zn2+-responsive contrast agent. Proc. Natl. Acad. Sci. USA 108, 18400–18405 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Arifin, D.R. & Bulte, J.W. Imaging of pancreatic islet cells. Diabetes Metab. Res. Rev. 27, 761–766 (2011).

    PubMed  PubMed Central  Google Scholar 

  123. Minger, S.L. et al. Endogenous neurogenesis in the human brain following cerebral infarction. Regen. Med. 2, 69–74 (2007).

    PubMed  Google Scholar 

  124. Donovan, T. et al. Stereotactic MR imaging for planning neural transplantation: a reliable technique at 3 Tesla? Br. J. Neurosurg. 17, 443–449 (2003).

    CAS  PubMed  Google Scholar 

  125. Kondziolka, D., Steinberg, G.K., Cullen, S.B. & McGrogan, M. Evaluation of surgical techniques for neuronal cell transplantation used in patients with stroke. Cell Transplant. 13, 749–754 (2004).

    PubMed  Google Scholar 

  126. Muir, K.W., Sinden, J., Miljan, E. & Dunn, L. Intracranial delivery of stem cells. Transl. Stroke Res. 2, 266–271 (2011).

    PubMed  Google Scholar 

  127. Lindvall, O. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 247, 574–577 (1990).

    CAS  PubMed  Google Scholar 

  128. Politis, M. et al. Serotonin neuron loss and nonmotor symptoms continue in Parkinson's patients treated with dopamine grafts. Sci. Transl. Med. 4, 128ra41 (2012).

    PubMed  Google Scholar 

  129. Politis, M. & Piccini, P. In vivo imaging of the integration and function of nigral grafts in clinical trials. Prog. Brain Res. 200, 199–220 (2012).

    PubMed  Google Scholar 

  130. Kondziolka, D. et al. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J. Neurosurg. 103, 38–45 (2005).

    PubMed  Google Scholar 

  131. Kondziolka, D. et al. Transplantation of cultured human neuronal cells for patients with stroke. Neurology 55, 565–569 (2000).

    CAS  PubMed  Google Scholar 

  132. Gupta, N. et al. Neural stem cell engraftment and myelination in the human brain. Sci. Transl. Med. 4, 155ra137 (2012).

    PubMed  PubMed Central  Google Scholar 

  133. Lee, P.H. et al. Autologous mesenchymal stem cell therapy delays the progression of neurological deficits in patients with multiple system atrophy. Clin. Pharmacol. Ther. 83, 723–730 (2008).

    CAS  PubMed  Google Scholar 

  134. Moniche, F. et al. Intra-arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke 43, 2242–2244 (2012).

    PubMed  Google Scholar 

  135. Rosado-de-Castro, P.H. et al. Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients. Regen. Med. 8, 145–155 (2013).

    CAS  PubMed  Google Scholar 

  136. Battistella, V. et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen. Med. 6, 45–52 (2011).

    CAS  PubMed  Google Scholar 

  137. Lazaridou, A. et al. fMRI as a molecular imaging procedure for the functional reorganization of motor systems in chronic stroke. Mol. Med. Rep. 8, 775–779 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Ross, B.D. et al. In vivo magnetic resonance spectroscopy of human fetal neural transplants. NMR Biomed. 12, 221–236 (1999).

    CAS  PubMed  Google Scholar 

  139. Chung, Y.L. et al. Profiling metabolite changes in the neuronal differentiation of human striatal neural stem cells using 1H-magnetic resonance spectroscopy. Neuroreport 24, 1035–1040 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Piccini, P. et al. Dopamine release from nigral transplants visualized in vivo in a Parkinson's patient. Nat. Neurosci. 2, 1137–1140 (1999).

    CAS  PubMed  Google Scholar 

  141. Kefalopoulou, Z. et al. Long-term clinical outcome of fetal cell transplantation for Parkinson disease: two case reports. JAMA Neurol. 71, 83–87 (2014).

    PubMed  PubMed Central  Google Scholar 

  142. Politis, M. et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson's patients with neural transplants. Sci. Transl. Med. 2, 38ra46 (2010).

    PubMed  Google Scholar 

  143. Bernard-Gauthier, V., Boudjemeline, M., Rosa-Neto, P., Thiel, A. & Schirrmacher, R. Towards tropomyosin-related kinase B (TrkB) receptor ligands for brain imaging with PET: radiosynthesis and evaluation of 2-(4-[(18)F]fluorophenyl)-7,8-dihydroxy-4H-chromen-4-one and 2-(4-([N-methyl-(11)C]-dimethylamino)phenyl)-7,8-dihydroxy-4H-chromen-4-one. Bioorg. Med. Chem. 21, 7816–7829 (2013).

    CAS  PubMed  Google Scholar 

  144. Sztriha, L.K. et al. Monitoring brain repair in stroke using advanced magnetic resonance imaging. Stroke 43, 3124–3131 (2012).

    PubMed  Google Scholar 

  145. Wardlaw, J.M. et al. Clinical relevance and practical implications of trials of perfusion and angiographic imaging in patients with acute ischaemic stroke: a multicentre cohort imaging study. J. Neurol. Neurosurg. Psychiatry 84, 1001–1007 (2013).

    PubMed  Google Scholar 

  146. Gerhard, A., Schwarz, J., Myers, R., Wise, R. & Banati, R.B. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage 24, 591–595 (2005).

    PubMed  Google Scholar 

  147. Saleh, A. et al. Iron oxide particle-enhanced MRI suggests variability of brain inflammation at early stages after ischemic stroke. Stroke 38, 2733–2737 (2007).

    PubMed  Google Scholar 

  148. Rueger, M.A. et al. Noninvasive imaging of endogenous neural stem cell mobilization in vivo using positron emission tomography. J. Neurosci. 30, 6454–6460 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Rueger, M.A. et al. Effects of minocycline on endogenous neural stem cells after experimental stroke. Neuroscience 215, 174–183 (2012).

    CAS  PubMed  Google Scholar 

  150. Meltzer, C.C. et al. Serial [18F] fluorodeoxyglucose positron emission tomography after human neuronal implantation for stroke. Neurosurgery 49, 586–591 (2001).

    CAS  PubMed  Google Scholar 

  151. Modo, M., Ambrosio, F., Friedlander, R.M., Badylak, S.F. & Wechsler, L.R. Bioengineering solutions for neural repair and recovery in stroke. Curr. Opin. Neurol. 26, 626–631 (2013).

    CAS  PubMed  Google Scholar 

  152. Park, K.I., Teng, Y.D. & Snyder, E.Y. The injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue. Nat. Biotechnol. 20, 1111–1117 (2002).

    CAS  PubMed  Google Scholar 

  153. Yannas, I.V. Emerging rules for inducing organ regeneration. Biomaterials 34, 321–330 (2013).

    CAS  PubMed  Google Scholar 

  154. Bible, E. et al. Attachment of stem cells to scaffold particles for intra-cerebral transplantation. Nat. Protoc. 4, 1440–1453 (2009).

    CAS  PubMed  Google Scholar 

  155. Bible, E. et al. The support of neural stem cells transplanted into stroke-induced brain cavities by PLGA particles. Biomaterials 30, 2985–2994 (2009).

    CAS  PubMed  Google Scholar 

  156. Bible, E. et al. Non-invasive imaging of transplanted human neural stem cells and ECM scaffold remodeling in the stroke-damaged rat brain by (19)F- and diffusion-MRI. Biomaterials 33, 2858–2871 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Modo, M. et al. Considerations for the clinical use of contrast agents for cellular MRI in regenerative medicine. Contrast Media Mol. Imaging 8, 439–455 (2013).

    CAS  PubMed  Google Scholar 

  158. Josephson, L. & Rudin, M. Barriers to clinical translation with diagnostic drugs. J. Nucl. Med. 54, 329–332 (2013).

    CAS  PubMed  Google Scholar 

  159. Molina, D.K. & DiMaio, V.J. Normal organ weights in men: part II-the brain, lungs, liver, spleen, and kidneys. Am. J. Forensic Med. Pathol. 33, 368–372 (2012).

    PubMed  Google Scholar 

  160. Molina, D.K. & DiMaio, V.J. Normal organ weights in men: part I-the heart. Am. J. Forensic Med. Pathol. 33, 362–367 (2012).

    PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge Kristine Evers for proofreading of the manuscript and the following grant support: M.M. was supported by the Commonwealth of Pennsylvania, Department of Health (4100061184), NINDS (R01NS082226) and NIBIB (1R01EB016629). C.E.M. was supported by US National Institutes of Health (NIH) grants P01HL094374, R01HL084642, U01HL100405 and P01GM81619. J.A.F. was supported in part by the intramural research program in the Clinical Center and National Institutes of Biomedical Imaging and Bioengineering at the US National Institutes of Health. A.M. was supported in part by NIH grant R24 DK096465.

Author information

Authors and Affiliations

  1. Department of Radiology, University of Washington, Seattle, Washington, USA

    Anna V Naumova

  2. Center for Cardiovascular Biology, University of Washington, Seattle, Washington, USA

    Anna V Naumova & Charles E Murry

  3. Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, USA

    Anna V Naumova & Charles E Murry

  4. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Michel Modo

  5. Centre for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Michel Modo

  6. Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Michel Modo

  7. Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Michel Modo

  8. Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA

    Anna Moore

  9. Department of Pathology, University of Washington, Seattle, Washington, USA

    Charles E Murry

  10. Department of Bioengineering, University of Washington, Seattle, Washington, USA

    Charles E Murry

  11. Department of Medicine/Cardiology, University of Washington, Seattle, Washington, USA

    Charles E Murry

  12. Radiology and Imaging Sciences, Clinical, National Institutes of Health, Bethesda, Maryland, USA

    Joseph A Frank

  13. National Institutes of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA

    Joseph A Frank

Authors
  1. Anna V Naumova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michel Modo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles E Murry
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joseph A Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Charles E Murry or Joseph A Frank.

Ethics declarations

Competing interests

C.E.M. is a scientific founder and equity holder in BEAT Biotherapeutics.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Naumova, A., Modo, M., Moore, A. et al. Clinical imaging in regenerative medicine. Nat Biotechnol 32, 804–818 (2014). https://doi.org/10.1038/nbt.2993

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nbt.2993

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing