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Blood, 15 June 2008, Vol. 111, No. 12, pp. 5544-5552.
Prepublished online as a Blood First Edition Paper on February 11, 2008; DOI 10.1182/blood-2007-10-119073.


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HEMATOPOIESIS AND STEM CELLS

The combination of granulocyte colony-stimulating factor and stem cell factor significantly increases the number of bone marrow–derived endothelial cells in brains of mice following cerebral ischemia

Zsuzsanna E. Toth1,*, Ronen R. Leker2,*, Tal Shahar2,*, Sandra Pastorino3, Ildiko Szalayova1, Brook Asemenew1, Sharon Key1, Alissa Parmelee1, Balazs Mayer1, Krisztian Nemeth1, Andras Bratincsák4, and Éva Mezey1

1 National Institute of Dental and Craniofacial Research, Bethesda, MD; 2 National Institute of Neurological Disorders and Stroke, Bethesda, MD; 3 National Cancer Institute, Bethesda, MD; and 4 National Institute of Mental Health, National Insitutes of Health, Bethesda, MD

Granulocyte colony-stimulating factor (G-CSF) induces proliferation of bone marrow–derived cells. G-CSF is neuroprotective after experimental brain injury, but the mechanisms involved remain unclear. Stem cell factor (SCF) is a cytokine important for the survival and differentiation of hematopoietic stem cells. Its receptor (c-kit or CD117) is present in some endothelial cells. We aimed to determine whether the combination of G-CSF/SCF induces angiogenesis in the central nervous system by promoting entry of endothelial precursors into the injured brain and causing them to proliferate there. We induced permanent middle cerebral artery occlusion in female mice that previously underwent sex-mismatched bone marrow transplantation from enhanced green fluorescent protein (EGFP)–expressing mice. G-CSF/SCF treatment reduced infarct volumes by more than 50% and resulted in a 1.5-fold increase in vessel formation in mice with stroke, a large percentage of which contain endothelial cells of bone marrow origin. Most cells entering the brain maintained their bone marrow identity and did not transdifferentiate into neural cells. G-CSF/SCF treatment also led to a 2-fold increase in the number of newborn cells in the ischemic hemisphere. These findings suggest that G-CSF/SCF treatment might help recovery through induction of bone marrow–derived angiogenesis, thus improving neuronal survival and functional outcome.


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