Article | Published:

Control of cerebral ischemia with magnetic nanoparticles

Nature Methods volume 14, pages 160166 (2017) | Download Citation

  • A Corrigendum to this article was published on 27 April 2017

This article has been updated

Abstract

The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.

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Change history

  • 10 April 2017

    In the version of this article initially published, the middle cerebral artery was incorrectly referred to as the middle carotid artery. The error has been corrected in the HTML and PDF versions of the article as of 10 April 2017.

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Acknowledgements

We thank W.Z. Sun, L.J. Wu, H. Lü, and L.J. He for advice on live imaging; J. Zheng and A. Fu for advice on MPs; M. Dellinger for advice on H.E. staining; D. Xu and H. Cai for advice on MRI; B. Zhou, I. Shimada, M. Acar, and M. Chen for input concerning SMCs, MCAO and FJC staining; W.L. Du's input for MCAO surgery; T. Taylor, H. Zhu, J.D. Chen, Z.H. Zhang, Z.P. Hu, G.E. Cai, M. Goldberg, F. Chen, L. Smith, and J. Long as well as colleagues at CRI for critical discussion and reading of the manuscript. This work is supported by the National Basic Research Program of China (No. 2015CB352006) and the Science Fund for Creative Research Group of China (No. 61121004) to W.Z.; CRI start-up funds and NINDS K99/R00 (R00NS073735) to W.-P.G.; NIH Director's New Innovator Award (DP2-NS082125) to B. Cui, American Heart Association (14SDG18410020) and NINDS (NS088555) to A.M.S.; and the Dr. Jack Krohmer Professorship in Radiation Physics for X.S. W.-P.G. is a recipient of an NINDS Pathway to Independence Award. W.L. is a recipient of an American Heart Association Postdoctoral Fellowship Award.

Author information

Affiliations

  1. Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Jie-Min Jia
    • , Xiaofei Gao
    • , Bo Ci
    •  & Woo-Ping Ge
  2. Department of Chemistry, Stanford University, Stanford, California, USA.

    • Praveen D Chowdary
    •  & Bianxiao Cui
  3. Center for Neuroscience Discovery, University of North Texas Health Science Center, Fort Worth, Texas, USA.

    • Wenjun Li
    •  & Shao-Hua Yang
  4. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Aditi Mulgaonkar
    • , Gedaa Hassan
    • , Amit Kumar
    •  & Xiankai Sun
  5. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Erik J Plautz
    •  & Ann M Stowe
  6. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-HuaZhong University of Science and Technology, Wuhan, China.

    • Wei Zhou
  7. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Woo-Ping Ge
  8. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Woo-Ping Ge
  9. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Woo-Ping Ge

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Contributions

W.-P.G., B. Cui, and J.-M.J. conceived the project, and J.-M.J. performed most of the animal experiments and analyzed data. P.D.C. characterized properties of magnets. W.-P.G., X.G., B. Ci, E.J.P., W.L., A.M., G.H., A.K., and W.Z. performed the other experiments. W.-P.G., J.-M.J., P.D.C., X.G., B. Cui, X.S., A.M.S., and S.-H.Y. designed the experiments. W.-P.G., J.-M.J., X.G., P.D.C., B. Cui, A.M., and G.H. wrote the manuscript. All authors reviewed and edited the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Bianxiao Cui or Woo-Ping Ge.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–14 and Supplementary Table 1.

Videos

  1. 1.

    Reversible occlusion of blood vessels.

    Occlusion of an artery as produced by a 0.5-mm micro-magnet. Reperfusion began within seconds once the magnet was removed (black, upper left).

  2. 2.

    Blood cells flowing through blood vessels.

    Cell from whole blood (~10–20 μl, see details in Methods) were labeled with DiO dye (green) and then injected into the tail vein of the same mouse.

  3. 3.

    Loss of SMCs during occlusion in arteries/arterioles.

    SMCs were gradually lost during occlusion of arteries/arterioles from a juvenile mouse. Length of video, 1 h. Red, DsRed fluorescence in NG2DsRedBACtg mice.

  4. 4.

    Blebbing in SMCs after blood occlusion.

    Cells from whole blood (~10–20 μl) were labeled with DiO dye (green) and then injected back into the tail vein of the same mouse. Note that one blood cell cleared a SMC shortly after its blebbing. Red, DsRed fluorescencein NG2DsRedBACtg mice. Length of video, 1 h, 54 min.

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DOI

https://doi.org/10.1038/nmeth.4105

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