Transplanted stem cell-secreted VEGF effects post-stroke recovery, inflammation, and vascular repair

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 sub-acute transplantation into the ischemic brain of human central nervous system stem cells grown as neurospheres (hCNS-SCns), the stem cell-secreted factor, human VEGF (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 (BBB) integrity and suppression of inflammation was followed by a delayed spatio-temporal regulated increase in neovascularization. These events coincided with a bi-modal pattern of functional recovery: an early recovery independent of neovascularization, and a delayed hVEGFdependent recovery coincident with neovascularization. Therefore, cell transplantation therapy Correspondence and requests for reprints to: Tonya Bliss, PhD, [email protected], Dept Neurosurgery, 1201 Welch Rd, Stanford, CA 94305-5487, USA, Tel: +1 650 723 2004, Fax: +1 650 736 1949 or Gary K. Steinberg, MD, PhD, [email protected], Dept Neurosurgery, 1201 Welch Rd, Stanford, CA 94305-5487, USA, Tel: +1 650 725 5562, Fax: +1 650 723 2815. *These authors contributed equally to this work **Co-senior authors Nobutaka Horie has moved to the Department of Neurosurgery, Nagasaki University School of Medicine, 1-7-1, Sakamoto, Nagasaki, Japan, 852-8501 Disclosure of Potential Conflicts of Interest: S.H. is a full time employee of StemCells Inc, the company that provided the cells, and has equity (stock) in the company. The other authors have no financial interests to disclose. Author Contributions: Nobutaka Horie: Design, collection and assembly of data, data analysis and interpretation, manuscript writing Kuniyasu Niizuma: Collection and assembly of data, data analysis and interpretation Marta P. Pereira: Design, collection and assembly of data, data analysis and interpretation, manuscript writing Guohua Sun: Collection of data Hadar Keren-Gill: Collection of data Angelo Encarnacion: Collection of data Mehrdad Shamloo: Collection of data Scott A. Hamilton: Statistical analysis advice Kewen Jiang: Collection of data Stephen Huhn: Provision of study material, manuscript writing Theo D. Palmer: Data analysis and interpretation Tonya M. Bliss: Conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript Gary K. Steinberg: Financial support, design, data interpretation, manuscript writing, final approval of manuscript NIH Public Access Author Manuscript Stem Cells. Author manuscript; available in PMC 2012 December 18. Published in final edited form as: Stem Cells. 2011 February ; 29(2): . doi:10.1002/stem.584. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript offers an exciting multi-modal strategy for brain repair in stroke and potentially other disorders with a vascular or inflammatory component.