Article

Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy

  • Nature Nanotechnology volume 12, pages 10061014 (2017)
  • doi:10.1038/nnano.2017.133
  • Download Citation
Received:
Accepted:
Published online:

Abstract

Electromagnetic fields (EMF) are physical energy fields generated by electrically charged objects, and specific ranges of EMF can influence numerous biological processes, which include the control of cell fate and plasticity. In this study, we show that electromagnetized gold nanoparticles (AuNPs) in the presence of specific EMF conditions facilitate an efficient direct lineage reprogramming to induced dopamine neurons in vitro and in vivo. Remarkably, electromagnetic stimulation leads to a specific activation of the histone acetyltransferase Brd2, which results in histone H3K27 acetylation and a robust activation of neuron-specific genes. In vivo dopaminergic neuron reprogramming by EMF stimulation of AuNPs efficiently and non-invasively alleviated symptoms in mouse Parkinson's disease models. This study provides a proof of principle for EMF-based in vivo lineage conversion as a potentially viable and safe therapeutic strategy for the treatment of neurodegenerative disorders.

  • Subscribe to Nature Nanotechnology for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    et al. Calcium homeostasis and low-frequency magnetic and electric field exposure: a systematic review and meta-analysis of in vitro studies. Environ. Int. 92-93, 695–706 (2016).

  2. 2.

    National Institute of Environmental Health Sciences and National Institutes of Health EMF Electric and Magnetic Fields Associated with the Use of Electric Power (NIEHS/DOE EMF Rapid Program, 2002).

  3. 3.

    , , & Low frequency EMF regulates chondrocyte differentiation and expression of matrix proteins. J. Orthop. Res. 20, 40–50 (2002).

  4. 4.

    et al. Effects of electromagnetic fields on proteoglycan metabolism of bovine articular cartilage explants. Connect. Tissue Res. 44, 154–159 (2003).

  5. 5.

    , & Electromagnetic effects—from cell biology to medicine. Prog. Histochem. Cytochem. 43, 177–264 (2009).

  6. 6.

    et al. Neural stimulation on human bone marrow-derived mesenchymal stem cells by extremely low frequency electromagnetic fields. Biotechnol. Prog. 28, 1329–1335 (2012).

  7. 7.

    , & Egr1 mediated the neuronal differentiation induced by extremely low-frequency electromagnetic fields. Life Sci. 102, 16–27 (2014).

  8. 8.

    et al. Gene array analysis of neural crest cells identifies transcription factors necessary for direct conversion of embryonic fibroblasts into neural crest cells. Biol. Open 5, 311–322 (2016).

  9. 9.

    et al. Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463, 1035–1041 (2010).

  10. 10.

    et al. Direct lineage conversion of terminally differentiated hepatocytes to functional neurons. Cell Stem Cell 9, 374–382 (2011).

  11. 11.

    et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).

  12. 12.

    et al. Functional integration of dopaminergic neurons directly converted from mouse fibroblasts. Cell Stem Cell 9, 413–419 (2011).

  13. 13.

    et al. Generation of induced neurons via direct conversion in vivo. Proc. Natl Acad. Sci. USA 110, 7038–7043 (2013).

  14. 14.

    et al. In vivo direct reprogramming of reactive glial cells into functional neurons after brain injury and in an Alzheimer's disease model. Cell Stem Cell 14, 188–202 (2014).

  15. 15.

    Applications of nanoparticles in biology and medicine. J. Nanobiotechnol. 2, 3 (2004).

  16. 16.

    et al. Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell 158, 889–902 (2014).

  17. 17.

    et al. Generation of induced neuronal cells by the single reprogramming factor ASCL1. Stem Cell Rep. 3, 282–296 (2014).

  18. 18.

    et al. Direct conversion of normal and Alzheimer's disease human fibroblasts into neuronal cells by small molecules. Cell Stem Cell 17, 204–212 (2015).

  19. 19.

    et al. Small-molecule-driven direct reprogramming of mouse fibroblasts into functional neurons. Cell Stem Cell 17, 195–203 (2015).

  20. 20.

    et al. Schwann-like cells differentiated from human dental pulp stem cells combined with a pulsed electromagnetic field can improve peripheral nerve regeneration. Bioelectromagnetics 37, 163–174 (2016).

  21. 21.

    , & The double bromodomain proteins Brd2 and Brd3 couple histone acetylation to transcription. Mol. Cell 30, 51–60 (2008).

  22. 22.

    et al. In vivo reprogramming of striatal NG2 glia into functional neurons that integrate into local host circuitry. Cell Rep. 12, 474–481.

  23. 23.

    , , , & Extremely low frequency electromagnetic fields (ELF-EMFs) induce in vitro angiogenesis process in human endothelial cells. Bioelectromagnetics 29, 640–648 (2008).

  24. 24.

    , , & Effects of 50 Hz EMF exposure on micronucleus formation and apoptosis in transformed and nontransformed human cell lines. Bioelectromagnetics 19, 85–91 (1998).

  25. 25.

    & Electromagnetic fields stress living cells. Pathophysiology 16, 71–78 (2009).

  26. 26.

    et al. Electromagnetic fields mediate efficient cell reprogramming into a pluripotent state. ACS Nano 8, 10125–10138 (2014).

  27. 27.

    et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485, 593–598 (2012).

  28. 28.

    et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature 485, 599–604 (2012).

  29. 29.

    et al. Induction of functional dopamine neurons from human astrocytes in vitro and mouse astrocytes in a Parkinson's disease model. Nat. Biotechnol. 35, 444–452 (2017).

  30. 30.

    & Direct reprogramming of fibroblasts into myocytes to reverse fibrosis. Ann. Rev. Physiol. 76, 21–37 (2014).

  31. 31.

    , & Somatic cell reprogramming into cardiovascular lineages. J. Cardiovasc. Pharmacol. Ther. 19, 340–349 (2014).

  32. 32.

    et al. Schwann-like cells differentiated from human dental pulp stem cells combined with a pulsed electromagnetic field can improve peripheral nerve regeneration. Bioelectromagnetics 37, 163–174 (2016).

  33. 33.

    Accumulation of calcium ions in myocardial sarcoplasmic reticulum of restrained rats exposed to the pulsed electromagnetic field. Aviakosm. Ekolog. Med. 26, 49–51 (1991).

  34. 34.

    , & Kinetically controlled seeded growth synthesis of citrate-stabilized gold nanoparticles of up to 200 nm: size focusing versus Ostwald ripening. Langmuir 27, 11098–11105 (2011).

  35. 35.

    , & Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120 (2014).

  36. 36.

    , , & Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 10, R25 (2009).

  37. 37.

    , , , & deepTools: a flexible platform for exploring deep-sequencing data. Nucleic Acids Res. 42, W187–W191 (2014).

  38. 38.

    et al. Model-based analysis of ChIP-seq (MACS). Genome Biol. 9, 1 (2008).

  39. 39.

    , &, ChIPseeker: an R/Bioconductor package for ChIP peak annotation, comparison and visualization. Bioinformatics 31, 2382–2383 (2015).

  40. 40.

    et al. PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).

  41. 41.

    et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

  42. 42.

    et al. CellNet: network biology applied to stem cell engineering. Cell 158, 903–915 (2014).

Download references

Acknowledgements

This work was supported by the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (NRF-2017M3A9C6029306, 2016R1A2B2014195, 2013M3A9B4076483, NRF-2015 M3A9B4051064), Korea Health Technology R&D Project, Ministry of Health & Welfare (HI16C1176), the Next-Generation BioGreen 21 Program, Rural Development Administration (PJ011077) and the Ministry of Food and Drug Safety in 2017 (14172MFDS974).

Author information

Affiliations

  1. Laboratory of Stem Cells and Cell Reprogramming, Department of Biomedical Engineering (BK21 plus program), Dongguk University, Seoul 100-715, Republic of Korea

    • Junsang Yoo
    • , Hongwon Kim
    • , Yujung Chang
    • , Jaein Shin
    • , Soonbong Baek
    •  & Jongpil Kim
  2. Laboratory of Protein Engineering, Department of Biomedical Engineering, Dongguk University, Seoul 100-715, Republic of Korea

    • Euiyeon Lee
    •  & Youngeun Kwon
  3. Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu 45158, Republic of Korea

    • Hee Young Kim
  4. Department of Oral Physiology, School of Dentistry, Kyungpook National University, 2177, Dalgubeol Boulevard, Jung-gu, Daegu 41940, Republic of Korea

    • Dong-ho Youn
    • , Wonhee Jang
    •  & Won Jun
  5. Department of Life Science, Dongguk University, Seoul 188-26, Republic of Korea

    • Junghyun Jung
  6. College of Pharmacy, Kyung Hee University, Seoul 02447, Korea

    • Wonwoong Lee
    •  & Jongki Hong
  7. Department of Electrical and Electronic Engineering, Hankyong National University, Kyonggi-do 456-749, Republic of Korea

    • Soochan Kim
  8. Studies of Translational Acupuncture Research (STAR), Acupuncture & Meridian Science Research Center (AMSRC), Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 130-701, Republic of Korea

    • Hi-Joon Park
  9. Department of Biomedical Sciences, School of Veterinary Medicine and Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA

    • Christopher J. Lengner
  10. BIO-FD&C Co. 509-511, Smart Valley A, 30 Songdomirai-ro, Incheon 21990, Republic of Korea

    • Sang Hyun Moh

Authors

  1. Search for Junsang Yoo in:

  2. Search for Euiyeon Lee in:

  3. Search for Hee Young Kim in:

  4. Search for Dong-ho Youn in:

  5. Search for Junghyun Jung in:

  6. Search for Hongwon Kim in:

  7. Search for Yujung Chang in:

  8. Search for Wonwoong Lee in:

  9. Search for Jaein Shin in:

  10. Search for Soonbong Baek in:

  11. Search for Wonhee Jang in:

  12. Search for Won Jun in:

  13. Search for Soochan Kim in:

  14. Search for Jongki Hong in:

  15. Search for Hi-Joon Park in:

  16. Search for Christopher J. Lengner in:

  17. Search for Sang Hyun Moh in:

  18. Search for Youngeun Kwon in:

  19. Search for Jongpil Kim in:

Contributions

J.Y., Y.K. and J.K. designed the study. J.Y., E.L., H.Y.K., D.Y., J.J., H.K., Y.C., W.L., J.S., S.B., W.Jang, W.Jun, S.K., J.H. and H.P. performed the experiments. J.Y., J.K. and C.J.L. analysed the data. Y.K., E.L., H.Y.K., D.Y. and S.H.M. contributed materials and/or analysis tools. The manuscript was written based on contributions by all the authors. All the authors approved the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jongpil Kim.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information