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.

  • Technical Report
  • Published:

Remote regulation of glucose homeostasis in mice using genetically encoded nanoparticles

Nature Medicine volume 21, pages 92–98 (2015)Cite this article

Subjects

A Corrigendum to this article was published on 07 May 2015

This article has been updated

Abstract

Means for temporally regulating gene expression and cellular activity are invaluable for elucidating underlying physiological processes and would have therapeutic implications. Here we report the development of a genetically encoded system for remote regulation of gene expression by low-frequency radio waves (RFs) or a magnetic field. Iron oxide nanoparticles are synthesized intracellularly as a GFP-tagged ferritin heavy and light chain fusion. The ferritin nanoparticles associate with a camelid anti-GFP–transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression. In mice with stem cell or viral expression of these genetically encoded components, remote stimulation of insulin transgene expression with RF or a magnet lowers blood glucose. This robust, repeatable method for remote regulation in vivo may ultimately have applications in basic science, technology and therapeutics.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: In vitro optimization of gene expression and protein release with genetically encoded nanoparticles.
Figure 2: RF-regulated gene expression in vivo using MSCs.
Figure 3: RF-regulated gene expression in vivo using adenoviral delivery of transgenes.
Figure 4: Repeated RF treatment to regulate protein delivery.
Figure 5: Remote activation of gene expression with a static magnetic field.

Similar content being viewed by others

Change history

  • 20 February 2015

     In the version of this article initially published, the ferritin linker region was incorrectly described as HA-tagged. It was FLAG-tagged. Thus, the descriptions of its detection in the study and of the protocol used for its detection in the Online Methods were incorrect (including an incorrect reference for the associated antibody used). Also, the description of the development of the tag was missing from the Online Methods. The errors have been corrected in the HTML and PDF versions of the article.

References

  1. Davidson, B.L. & Breakefield, X.O. Viral vectors for gene delivery to the nervous system. Nat. Rev. Neurosci. 4, 353–364 (2003).

    Article  CAS  Google Scholar 

  2. Ando, H., Furuta, T., Tsien, R.Y. & Okamoto, H. Photo-mediated gene activation using caged RNA/DNA in zebrafish embryos. Nat. Genet. 28, 317–325 (2001).

    Article  CAS  Google Scholar 

  3. Cambridge, S.B., Davis, R.L. & Minden, J.S. Drosophila mitotic domain boundaries as cell fate boundaries. Science 277, 825–828 (1997).

    Article  CAS  Google Scholar 

  4. Wang, X., Chen, X. & Yang, Y. Spatiotemporal control of gene expression by a light-switchable transgene system. Nat. Methods 9, 266–269 (2012).

    Article  CAS  Google Scholar 

  5. Gossen, M. et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995).

    Article  CAS  Google Scholar 

  6. Danielian, P.S., Muccino, D., Rowitch, D.H., Michael, S.K. & McMahon, A.P. Modification of gene activity in mouse embryos in utero by a tamoxifen-inducible form of Cre recombinase. Curr. Biol. 8, 1323–1326 (1998).

    Article  CAS  Google Scholar 

  7. Böcker, R., Estler, C.J., Maywald, M. & Weber, D. Comparison of distribution of doxycycline in mice after oral and intravenous application measured by a high-performance liquid chromatographic method. Arzneimittelforschung 31, 2116–2117 (1981).

    PubMed  Google Scholar 

  8. Peters, R.W., Shafton, E., Frank, S., Thomas, A.N. & Scheinman, M.M. Radiofrequency-triggered pacemakers: uses and limitations. A long-term study. Ann. Intern. Med. 88, 17–22 (1978).

    Article  CAS  Google Scholar 

  9. Stanley, S.A. et al. Radiowave heating of iron oxide nanoparticles can regulate plasma glucose in mice. Science 336, 604–608 (2012).

    Article  CAS  Google Scholar 

  10. Huang, H., Delikanli, S., Zeng, H., Ferkey, D.M. & Pralle, A. Remote control of ion channels and neurons through magnetic-field heating of nanoparticles. Nat. Nanotechnol. 5, 602–606 (2010).

    Article  CAS  Google Scholar 

  11. Knight, L.C. et al. Binding and internalization of iron oxide nanoparticles targeted to nuclear oncoprotein. J. Mol. Biomark. Diagn. 1, 10000102 (2010).

    Article  Google Scholar 

  12. Iordanova, B., Robison, C.S. & Ahrens, E.T. Design and characterization of a chimeric ferritin with enhanced iron loading and transverse NMR relaxation rate. J. Biol. Inorg. Chem. 15, 957–965 (2010).

    Article  CAS  Google Scholar 

  13. Kirchhofer, A. et al. Modulation of protein properties in living cells using nanobodies. Nat. Struct. Mol. Biol. 17, 133–138 (2010).

    Article  CAS  Google Scholar 

  14. Hong, L., Peptan, I.A., Colpan, A. & Daw, J.L. Adipose tissue engineering by human adipose-derived stromal cells. Cells Tissues Organs 183, 133–140 (2006).

    Article  CAS  Google Scholar 

  15. Durand, J.L., Hosinking, W. & Jelicks, L.A. Time course of effects of inhalation anesthesia on blood glucose level in male and female C57BL/6 mice. Horm. Metab. Res. 41, 339–341 (2009).

    Article  CAS  Google Scholar 

  16. Tanaka, K. et al. Mechanisms of impaired glucose tolerance and insulin secretion during isoflurane anesthesia. Anesthesiology 111, 1044–1051 (2009).

    Article  CAS  Google Scholar 

  17. Vore, S.J., Aycock, E.D., Veldhuis, J.D. & Butler, P.C. Anesthesia rapidly suppresses insulin pulse mass but enhances the orderliness of insulin secretory process. Am. J. Physiol. Endocrinol. Metab. 281, E93–E99 (2001).

    Article  CAS  Google Scholar 

  18. Kawano, T. et al. Biophysical and pharmacological properties of glucagon-like peptide-1 in rats under isoflurane anesthesia. Anesth. Analg. 115, 62–69 (2012).

    Article  CAS  Google Scholar 

  19. Fortin, J.P., Gazeau, F. & Wilhelm, C. Intracellular heating of living cells through Néel relaxation of magnetic nanoparticles. Eur. Biophys. J. 37, 223–228 (2008).

    Article  CAS  Google Scholar 

  20. Liedtke, W. et al. Vanilloid receptor–related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103, 525–535 (2000).

    Article  CAS  Google Scholar 

  21. Gilles, C. et al. Magnetic hysteresis and superantiferromagnetism in ferritin nanoparticles. J. Magn. Magn. Mater. 241, 430–440 (2002).

    Article  CAS  Google Scholar 

  22. Johnsen, S. & Lohmann, K.J. The physics and neurobiology of magnetoreception. Nat. Rev. Neurosci. 6, 703–712 (2005).

    Article  CAS  Google Scholar 

  23. Arosio, P., Ingrassia, R. & Cavadini, P. Ferritins: a family of molecules for iron storage, antioxidation and more. Biochim. Biophys. Acta 1790, 589–599 (2009).

    Article  CAS  Google Scholar 

  24. Kim, T., Moore, D. & Fussenegger, M. Genetically programmed superparamagnetic behavior of mammalian cells. J. Biotechnol. 162, 237–245 (2012).

    Article  CAS  Google Scholar 

  25. Beyer, B.K., Stark, K.L., Fantel, A.G. & Juchau, M.R. Biotransformation, estrogenicity, and steroid structure as determinants of dysmorphogenic and generalized embryotoxic effects of steroidal and nonsteroidal estrogens. Toxicol. Appl. Pharmacol. 98, 113–127 (1989).

    Article  CAS  Google Scholar 

  26. Saxén, L. Drug-induced teratogenesis in vitro: inhibition of calcification by different tetracyclines. Science 153, 1384–1387 (1966).

    Article  Google Scholar 

  27. Fussenegger, M., Schlatter, S., Datwyler, D., Mazur, X. & Bailey, J.E. Controlled proliferation by multigene metabolic engineering enhances the productivity of Chinese hamster ovary cells. Nat. Biotechnol. 16, 468–472 (1998).

    Article  CAS  Google Scholar 

  28. Gadalla, K.K., Bailey, M.E. & Cobb, S.R. MeCP2 and Rett syndrome: reversibility and potential avenues for therapy. Biochem. J. 439, 1–14 (2011).

    Article  CAS  Google Scholar 

  29. Samaranayake, H., Wirth, T., Schenkwein, D., Raty, J.K. & Yla-Herttuala, S. Challenges in monoclonal antibody-based therapies. Ann. Med. 41, 322–331 (2009).

    Article  CAS  Google Scholar 

  30. Aleman, A. Use of repetitive transcranial magnetic stimulation for treatment in psychiatry. Clin. Psychopharmacol. Neurosci. 11, 53–59 (2013).

    Article  Google Scholar 

  31. Arenkiel, B.R., Klein, M.E., Davison, I.G., Katz, L.C. & Ehlers, M.D. Genetic control of neuronal activity in mice conditionally expressing TRPV1. Nat. Methods 5, 299–302 (2008).

    Article  CAS  Google Scholar 

  32. Lauwers, M. et al. An iron-rich organelle in the cuticular plate of avian hair cells. Curr. Biol. 23, 924–929 (2013).

    Article  CAS  Google Scholar 

  33. St Pierre, T.G. & Dobson, J. Theoretical evaluation of cell membrane ion channel activation by applied magnetic fields. Eur. Biophys. J. 29, 455–456 (2000).

    Article  CAS  Google Scholar 

  34. Kim, T., Moore, D. & Fussenegger, M. Genetically programmed superparamagnetic behavior of mammalian cells. J. Biotechnol. 162, 237–245 (2012).

    Article  CAS  Google Scholar 

  35. Hughes, S., McBain, S., Dobson, J. & El Haj, A.J. Selective activation of mechanosensitive ion channels using magnetic particles. J. R. Soc. Interface 5, 855–863 (2008).

    Article  CAS  Google Scholar 

  36. Gallego-Sandín, S., Rodriguez-Garcia, A., Alonso, M.T. & Garcia-Sancho, J. The endoplasmic reticulum of dorsal root ganglion neurons contains functional TRPV1 channels. J. Biol. Chem. 284, 32591–32601 (2009).

    Article  Google Scholar 

  37. Toriumi, K. et al. SHATI/NAT8L regulates neurite outgrowth via microtubule stabilization. J. Neurosci. Res. 91, 1525–1532 (2013).

    Article  CAS  Google Scholar 

  38. Collins, C.A., Kretzschmar, K. & Watt, F.M. Reprogramming adult dermis to a neonatal state through epidermal activation of β-catenin. Development 138, 5189–5199 (2011).

    Article  CAS  Google Scholar 

  39. Heins, N. et al. Emx2 promotes symmetric cell divisions and a multipotential fate in precursors from the cerebral cortex. Mol. Cell. Neurosci. 18, 485–502 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We would like to thank Friedman laboratory members for helpful discussions and S. Korres for assistance with preparation and submission of the manuscript. This work was funded by the Howard Hughes Medical Institute, the JPB Foundation, the US National Institutes of Health (GM095654) and a Rensselaer Fellowship (to J.S.) under a US National Institutes of Health predoctoral training grant (GM067545).

Author information

Author notes

  1. Sarah A Stanley and Jeremy Sauer: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Genetics, Rockefeller University, New York, New York, USA

    Sarah A Stanley & Jeffrey M Friedman

  2. Department of Chemical and Biological Engineering, Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York, USA

    Jeremy Sauer, Ravi S Kane & Jonathan S Dordick

  3. Howard Hughes Medical Institute, New York, New York, USA

    Jeffrey M Friedman

Authors
  1. Sarah A Stanley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremy Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ravi S Kane
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathan S Dordick
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey M Friedman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.M.F. conceived the project, and J.M.F. and J.S.D. supervised the studies. S.A.S. and J.S. designed and performed the experiments. R.S.K. provided technical advice. S.A.S., J.S., J.S.D. and J.M.F. wrote the manuscript.

Corresponding authors

Correspondence to Jonathan S Dordick or Jeffrey M Friedman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 (PDF 877 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stanley, S., Sauer, J., Kane, R. et al. Remote regulation of glucose homeostasis in mice using genetically encoded nanoparticles. Nat Med 21, 92–98 (2015). https://doi.org/10.1038/nm.3730

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3730

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