Skip to main content

Advertisement

Log in

Optical Imaging for Stem Cell Differentiation to Neuronal Lineage

  • Review
  • Published:
Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

In regenerative medicine, the prospect of stem cell therapy holds great promise for the recovery of injured tissues and effective treatment of intractable diseases. Tracking stem cell fate provides critical information to understand and evaluate the success of stem cell therapy. The recent emergence of in vivo noninvasive molecular imaging has enabled assessment of the behavior of grafted stem cells in living subjects. In this review, we provide an overview of current optical imaging strategies based on cell- or tissue-specific reporter gene expression and of in vivo methods to monitor stem cell differentiation into neuronal lineages. These methods use optical reporters either regulated by neuron-specific promoters or containing neuron-specific microRNA binding sites. Both systems revealed dramatic changes in optical reporter imaging signals in cells differentiating into a neuronal lineage. The detection limit of weak promoters or reporter genes can be greatly enhanced by adopting a yeast GAL4 amplification system or an engineering-enhanced luciferase reporter gene. Furthermore, we propose an advanced imaging system to monitor neuronal differentiation during neurogenesis that uses in vivo multiplexed imaging techniques capable of detecting several targets simultaneously.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Hipp J, Atala A. Sources of stem cells for regenerative medicine. Stem Cell Rev. 2008;4:3–11.

    Article  PubMed  Google Scholar 

  2. Sharp J, Keirstead HS. Stem cell-based cell replacement strategies for the central nervous system. Neurosci Lett. 2009;456:107–11.

    Article  PubMed  CAS  Google Scholar 

  3. Teo AK, Vallier L. Emerging use of stem cells in regenerative medicine. Biochem J. 2010;28:11–23.

    Article  Google Scholar 

  4. Cao F, Lin S, Xie X, Ray P, Patel M, Zhang X, et al. In vivo visualization of embryonic stem cell survival, proliferation, and migration after cardiac delivery. Circulation. 2006;113:1005–14.

    Article  PubMed  Google Scholar 

  5. Tang Y, Shah K, Messerli SM, Snyder E, Breakefield X, Weissleder R. In vivo tracking of neural progenitor cell migration to glioblastomas. Hum Gene Ther. 2003;14:1247–54.

    Article  PubMed  CAS  Google Scholar 

  6. Zhou R, Acton PD, Ferrari VA. Imaging stem cells implanted in infarcted myocardium. J Am Coll Cardiol. 2006;48:2094–106.

    Article  PubMed  Google Scholar 

  7. Baril P, Martin-Duque P, Vassaux G. Visualization of gene expression in the live subject using the Na/I symporter as a reporter gene: applications in biotherapy. Br J Pharmacol. 2010;159:61–71.

    Article  Google Scholar 

  8. Lucignani G. Molecular imaging is indispensable for the development of stem cell-based myocardial regenerative therapy. Eur J Nucl Med Mol Imaging. 2007;34:422–5.

    Article  PubMed  Google Scholar 

  9. Lee Z, Dennis JE, Gerson SL. Imaging stem cell implant for cellular-based therapies. Exp Biol Med (Maywood). 2008;233:930–40.

    Article  CAS  Google Scholar 

  10. Willmann JK, Paulmurugan R, Rodriguez-Porcel M, Stein W, Brinton TJ, Connolly AJ, et al. Imaging gene expression in human mesenchymal stem cells: from small to large animals. Radiology. 2009;252:117–27.

    Article  PubMed  Google Scholar 

  11. Serganova I, Blasberg R. Reporter gene imaging: potential impact on therapy. Nucl Med Biol. 2005;32:763–80.

    Article  PubMed  CAS  Google Scholar 

  12. Ponomarev V, Doubrovin M, Shavrin A, Serganova I, Beresten T, Ageyeva L, et al. A human-derived reporter gene for noninvasive imaging in humans: mitochondrial thymidine kinase type 2. J Nucl Med. 2007;48:819–26.

    Article  PubMed  CAS  Google Scholar 

  13. Loening AM, Dragulescu-Andrasi A, Gambhir SS. A red-shifted Renilla luciferase for transient reporter-gene expression. Nat Methods. 2010;7:5–6.

    Article  PubMed  CAS  Google Scholar 

  14. Yong J, Rasooly J, Dang H, Lu Y, Middleton B, Zhang Z, et al. Multimodality imaging of β-cells in mouse models of type 1 and 2 diabetes. Diabetes. 2011;60:1383–92.

    Article  PubMed  CAS  Google Scholar 

  15. Kang JH, Lee DS, Paeng JC, Lee JS, Kim YH, Lee YJ, et al. Development of a sodium/iodide symporter (NIS)-transgenic mouse for imaging of cardiomyocyte-specific reporter gene expression. J Nucl Med. 2005;46:479–83.

    PubMed  CAS  Google Scholar 

  16. Zhang R, Xue YY, Lu SD, Wang Y, Zhang LM, Huang YL, et al. Bcl-2 enhances neurogenesis and inhibits apoptosis of newborn neurons in adult rat brain following a transient middle cerebral artery occlusion. Neurobiol Dis. 2006;24:345–56.

    Article  PubMed  CAS  Google Scholar 

  17. Couillard-Despres S, Finkl R, Winner B, Ploetz S, Wiedermann D, Aigner R, et al. In vivo optical imaging of neurogenesis: watching new neurons in the intact brain. Mol Imaging. 2008;7:28–34.

    PubMed  CAS  Google Scholar 

  18. Mandel G, McKinnon D. Molecular basis of neural-specific gene expression. Annu Rev Neurosci. 1993;16:323–45.

    Article  PubMed  CAS  Google Scholar 

  19. Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, et al. Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004;24:2527–34.

    Article  PubMed  CAS  Google Scholar 

  20. Morelli AE, Larregina AT, Smith-Arica J, Dewey RA, Southgate TD, Ambar B, et al. Neuronal and glial cell type-specific promoters within adenovirus recombinants restrict the expression of the apoptosis-inducing molecule Fas ligand to predetermined brain cell types, and abolish peripheral liver toxicity. J Gen Virol. 1999;80:571–83.

    PubMed  CAS  Google Scholar 

  21. Hwang do W, Kang JH, Jeong JM, Chung JK, Lee MC, Kim S, et al. Noninvasive in vivo monitoring of neuronal differentiation using reporter driven by a neuronal promoter. Eur J Nucl Med Mol Imaging. 2008;35:135–45.

    Article  PubMed  Google Scholar 

  22. Ghil SH, Kim BJ, Lee YD, Suh-Kim H. Neurite outgrowth induced by cyclic AMP can be modulated by the alpha subunit of Go. J Neurochem. 2000;74:151–8.

    Article  PubMed  CAS  Google Scholar 

  23. Rabinovich BA, Ye Y, Etto T, Chen JQ, Levitsky HI, Overwijk WW, et al. Visualizing fewer than 10 mouse T cells with an enhanced firefly luciferase in immunocompetent mouse models of cancer. Proc Natl Acad Sci USA. 2008;105:14342–6.

    Article  PubMed  CAS  Google Scholar 

  24. Zhang L, Adams JY, Billick E, Ilagan R, Iyer M, Le K, et al. Molecular engineering of a two-step transcription amplification (TSTA) system for transgene delivery in prostate cancer. Mol Ther. 2002;5:223–32.

    Article  PubMed  CAS  Google Scholar 

  25. Sato M, Johnson M, Zhang L, Zhang B, Le K, Gambhir SS, et al. Optimization of adenoviral vectors to direct highly amplified prostate-specific expression for imaging and gene therapy. Mol Ther. 2003;8:726–37.

    Article  PubMed  CAS  Google Scholar 

  26. Ahn BC, Ronald JA, Kim YI, Katzenberg R, Singh A, Paulmurugan R, et al. Potent, tumor-specific gene expression in an orthotopic hepatoma rat model using a Survivin-targeted, amplifiable adenoviral vector. Gene Ther. 2011;18:606–12.

    Article  PubMed  CAS  Google Scholar 

  27. Chen IY, Gheysens O, Ray S, Wang Q, Padmanabhan P, Paulmurugan R, et al. Indirect imaging of cardiac-specific transgene expression using a bidirectional two-step transcriptional amplification strategy. Gene Ther. 2010;17:827–38.

    Article  PubMed  CAS  Google Scholar 

  28. Patel MR, Chang YF, Chen IY, Bachmann MH, Yan X, Contag CH, et al. Longitudinal, noninvasive imaging of T-cell effector function and proliferation in living subjects. Cancer Res. 2010;70:10141–9.

    Article  PubMed  CAS  Google Scholar 

  29. Shivdasani RA. MicroRNAs: regulators of gene expression and cell differentiation. Blood. 2006;108:3646–53.

    Article  PubMed  CAS  Google Scholar 

  30. Wienholds E, Plasterk RH. MicroRNA function in animal development. FEBS Lett. 2005;579:5911–22.

    Article  PubMed  CAS  Google Scholar 

  31. Saba R, Schratt GM. MicroRNAs in neuronal development, function and dysfunction. Brain Res. 2010;1338:3–13.

    Article  PubMed  CAS  Google Scholar 

  32. Jovanovic M, Hengartner MO. miRNAs and apoptosis: RNAs to die for. Oncogene. 2006;25:6176–87.

    Article  PubMed  CAS  Google Scholar 

  33. Shafi G, Aliya N, Munshi A. MicroRNA signatures in neurological disorders. Can J Neurol Sci. 2010;37:177–85.

    PubMed  Google Scholar 

  34. Gao Y, Schug J, McKenna LB, Le Lay J, Kaestner KH, Greenbaum LE. Tissue-specific regulation of mouse MicroRNA genes in endoderm-derived tissues. Nucleic Acids Res. 2011;39:454–63.

    Article  PubMed  CAS  Google Scholar 

  35. Roshan R, Ghosh T, Scaria V, Pillai B. MicroRNAs: novel therapeutic targets in neurodegenerative diseases. Drug Discov Today. 2009;14:1123–9.

    Article  PubMed  CAS  Google Scholar 

  36. De Smaele E, Ferretti E, Gulino A. MicroRNAs as biomarkers for CNS cancer and other disorders. Brain Res. 2010;1338:100–11.

    Article  PubMed  Google Scholar 

  37. Erson AE, Petty EM. miRNAs and cancer: New research developments and potential clinical applications. Cancer Biol Ther. 2009;8:2317–22.

    PubMed  CAS  Google Scholar 

  38. Kim HJ, Chung JK, Hwang do W, Lee DS, Kim S. In vivo imaging of miR-221 biogenesis in papillary thyroid carcinoma. Mol Imaging Biol. 2009;11:71–8.

    Article  PubMed  Google Scholar 

  39. Tani S, Kusakabe R, Naruse K, Sakamoto H, Inoue K. Genomic organization and embryonic expression of miR-430 in medaka (Oryzias latipes): insights into the post-transcriptional gene regulation in early development. Gene. 2010;449:41–9.

    Article  PubMed  CAS  Google Scholar 

  40. Ko MH, Kim S. Hwang do W, Ko HY, Kim YH, Lee DS. Bioimaging of the unbalanced expression of microRNA9 and microRNA9* during the neuronal differentiation of P19 cells. FEBS J. 2008;75:605–16.

    Google Scholar 

  41. Krichevsky AM, Sonntag KC, Isacson O, Kosik KS. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells. 2006;24:57–64.

    Article  Google Scholar 

  42. Smirnova L, Gräfe A, Seiler A, Schumacher S, Nitsch R, Wulczyn FG. Regulation of miRNA expression during neural cell specification. Eur J Neurosci. 2005;21:1469–77.

    Article  PubMed  Google Scholar 

  43. Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V. Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol. 2004;5:R13.1-11.

    Google Scholar 

  44. Ko HY. Hwang do W, Lee DS, Kim S. A reporter gene imaging system for monitoring microRNA biogenesis. Nat Protoc. 2009;4:1663–9.

    Article  PubMed  CAS  Google Scholar 

  45. Fukuda S, Taga T. Cell fate determination regulated by a transcriptional signal network in the developing mouse brain. Anat Sci Int. 2005;80:12–8.

    Article  PubMed  CAS  Google Scholar 

  46. Ohsawa R, Kageyama R. Regulation of retinal cell fate specification by multiple transcription factors. Brain Res. 2008;1192:90–8.

    Article  PubMed  CAS  Google Scholar 

  47. Li X, Jin P. Roles of small regulatory RNAs in determining neuronal identity. Nat Rev Neurosci. 2010;1:29–38.

    CAS  Google Scholar 

  48. Zavaleta CL, Smith BR, Walton I, Doering W, Davis G, Shojaei B, et al. Multiplexed imaging of surface enhanced Raman scattering nanotags in living mice using noninvasive Raman spectroscopy. Proc Natl Acad Sci USA. 2009;06:3511–6.

    Google Scholar 

  49. Yu KN, Lee SM, Han JY, Park H, Woo MA, Noh MS, et al. Multiplex targeting, tracking, and imaging of apoptosis by fluorescent surface enhanced Raman spectroscopic dots. Bioconjug Chem. 2007;8:155–62.

    Google Scholar 

  50. Woo MA, Lee SM, Kim G, Baek J, Noh MS, Kim JE, et al. Multiplex immunoassay using fluorescent-surface enhanced Raman spectroscopic dots for the detection of bronchioalveolar stem cells in murine lung. Anal Chem. 2009;81:1008–15.

    Article  PubMed  CAS  Google Scholar 

  51. Noh MS, Jun BH, Kim S, Kang H, Woo MA, Minai-Tehrani A, et al. Magnetic surface-enhanced Raman spectroscopic (M-SERS) dots for the identification of bronchioalveolar stem cells in normal and lung cancer mice. Biomaterials. 2009;30:3915–25.

    Article  PubMed  CAS  Google Scholar 

  52. Liu Z, Tabakman S, Sherlock S, Li X, Chen Z, Jiang K, et al. Multiplexed five-color molecular imaging of cancer cells and tumor tissues with carbon nanotube Raman tags in the near-infrared. Nano Res. 2010;3:222–33.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the Nanobiotechnology Project (Regenomics, no. 20100002086), the Brain Research Center of the 21st Century Frontier Research Program (2009K001257), the WCU project of the MEST, the NRF (R31-2008-000-10103-0), and the National Research Foundation of Korea grant (2011-0019044) funded by the Korean government (MEST). This research was performed as a collaborative research project of project no. C11007 (Study for Building and Service Implementation of Future Cyber-Infrastructure Resources environment) and supported by the Korea Institute of Science and Technology Information (KISTI).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dong Soo Lee.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hwang, D.W., Lee, D.S. Optical Imaging for Stem Cell Differentiation to Neuronal Lineage. Nucl Med Mol Imaging 46, 1–9 (2012). https://doi.org/10.1007/s13139-011-0122-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13139-011-0122-8

Keywords

Navigation