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

Authors

  • Nobutaka Horie,

    1. Department of Neurosurgery and Stanford Stroke Center, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA
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    • N.H. and M.P.P. contributed equally to this article.

  • Marta P. Pereira,

    1. Department of Neurosurgery and Stanford Stroke Center, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA
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    • N.H. and M.P.P. contributed equally to this article.

  • Kuniyasu Niizuma,

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

    1. Department of Neurosurgery and Stanford Stroke Center, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA
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  • Hadar Keren-Gill,

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

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

    1. Department of Neurosurgery and Stanford Stroke Center, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA
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  • Scott A. Hamilton,

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

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

    1. StemCells Inc., Palo Alto, California, USA
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  • Theo D. Palmer,

    1. Department of Neurosurgery and Stanford Stroke Center, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA
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  • Tonya M. Bliss,

    Corresponding author
    1. Department of Neurosurgery and Stanford Stroke Center, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA
    • Department of Neurosurgery, 1,201 Welch Rd, Stanford, California 94305-5487, USA
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    • Telephone: 1-650-723-2004; Fax: 1-650-736-1949

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

  • Gary K. Steinberg

    Corresponding author
    1. Department of Neurosurgery and Stanford Stroke Center, Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford University School of Medicine, Stanford, California, USA
    • Department of Neurosurgery, 300 Pasteur Drive, Room R-281, Stanford, California 94305-5487, USA
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    • T.M.B. and G.K.S. are the cosenior authors of this work.

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


  • 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.

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

  • §

    First published online in STEM CELLSEXPRESS January 14, 2011.

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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