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Transplanted Stem Cell-Secreted Vascular Endothelial Growth Factor Effects Poststroke Recovery, Inflammation, and Vascular Repair†‡§

  1. Nobutaka Horie1,¶,
  2. Marta P. Pereira1,¶,
  3. Kuniyasu Niizuma1,
  4. Guohua Sun1,
  5. Hadar Keren-Gill1,
  6. Angelo Encarnacion1,
  7. Mehrdad Shamloo1,
  8. Scott A. Hamilton1,
  9. Kewen Jiang1,
  10. Stephen Huhn2,
  11. Theo D. Palmer1,
  12. Tonya M. Bliss1,‖,††,*,
  13. Gary K. Steinberg1,‡‡,††,*

Article first published online: 24 FEB 2011

DOI: 10.1002/stem.584

Issue

STEM CELLS

STEM CELLS

Volume 29, Issue 2, pages 274–285, February 2011

Additional Information

How to Cite

Horie, N., Pereira, M. P., Niizuma, K., Sun, G., Keren-Gill, H., Encarnacion, A., Shamloo, M., Hamilton, S. A., Jiang, K., Huhn, S., Palmer, T. D., Bliss, T. M. and Steinberg, G. K. (2011), Transplanted Stem Cell-Secreted Vascular Endothelial Growth Factor Effects Poststroke Recovery, Inflammation, and Vascular Repair. STEM CELLS, 29: 274–285. doi: 10.1002/stem.584

Author Information

  1. 1

    Department of Neurosurgery and Stanford Stroke Center, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA

  2. 2

    StemCells Inc., Palo Alto, California, USA

  1. N.H. and M.P.P. contributed equally to this article.

  2. ‖

    Telephone: 1-650-723-2004; Fax: 1-650-736-1949

  3. ††

    T.M.B. and G.K.S. are the cosenior authors of this work.

  4. ‡‡

    Telephone: 1-650-725-5562; Fax: 1-650-723-2815

*Department of Neurosurgery, 1,201 Welch Rd, Stanford, California 94305-5487, USA

  1. †

    Author contributions: N.H.: design, collection, and assembly of data, data analysis and interpretation, manuscript writing; M.P.P.: design, collection, and assembly of data, data analysis and interpretation, manuscript writing; K.N.: collection and assembly of data, data analysis and interpretation; G.S.: collection of data; H.K.-G.: collection of data; A.E.: collection of data; M.S.: collection of data; S.A.H.: statistical analysis advice; K.J.: collection of data; S.H.: provision of study material, manuscript writing; T.D.P.: data analysis and interpretation; T.M.B.: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript; G.K.S.: financial support, design, data interpretation, manuscript writing, final approval of manuscript.

  2. ‡

    Disclosure of potential conflicts of interest is found at the end of this article.

  3. §

    First published online in STEM CELLSEXPRESS January 14, 2011.

  4. N.H. and M.P.P. contributed equally to this article.

  5. ‖

    Telephone: 1-650-723-2004; Fax: 1-650-736-1949

  6. ††

    T.M.B. and G.K.S. are the cosenior authors of this work.

  7. ‡‡

    Telephone: 1-650-725-5562; Fax: 1-650-723-2815

Publication History

  1. Issue published online: 24 FEB 2011
  2. Article first published online: 24 FEB 2011
  3. Accepted manuscript online: 14 JAN 2011 12:27PM EST
  4. Manuscript Accepted: 23 NOV 2010
  5. Manuscript Received: 5 MAR 2010

Funded by

  • National Institutes of Health National Institute of Neurological Disorders and Stroke. Grant Numbers: NS058784, NS27292, NS37520
  • William Randolph Hearst Foundation, Bernard and Ronni Lacroute, Russell and Elizabeth Siegelman, and the Edward E. Hills Fund
  • Ministry of Education and Science of Spain (reference 2007-1219)

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Keywords:

  • Angiogenesis;
  • Blood-brain barrier;
  • Dystroglycan;
  • Inflammation;
  • Avastin

Abstract

Cell transplantation offers a novel therapeutic strategy for stroke; however, how transplanted cells function in vivo is poorly understood. We show for the first time that after subacute transplantation into the ischemic brain of human central nervous system stem cells grown as neurospheres (hCNS-SCns), the stem cell-secreted factor, human vascular endothelial growth factor (hVEGF), is necessary for cell-induced functional recovery. We correlate this functional recovery to hVEGF-induced effects on the host brain including multiple facets of vascular repair and its unexpected suppression of the inflammatory response. We found that transplanted hCNS-SCns affected multiple parameters in the brain with different kinetics: early improvement in blood-brain barrier integrity and suppression of inflammation was followed by a delayed spatiotemporal regulated increase in neovascularization. These events coincided with a bimodal pattern of functional recovery, with, an early recovery independent of neovascularization, and a delayed hVEGF-dependent recovery coincident with neovascularization. Therefore, cell transplantation therapy offers an exciting multimodal strategy for brain repair in stroke and potentially other disorders with a vascular or inflammatory component. STEM CELLS 2011;29:274–285

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