Claudia Pösel1, Johanna Scheibe2, Alexander Kranz2, Viktoria Bothe2, Elfi Quente2, Wenke Fröhlich2, Franziska Lange2, Wolf-Rüdiger Schäbitz2, Jens Minnerup2, Johannes Boltze2, Daniel-Christoph Wagner2. 1. From the Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany (C.P., J.S., A.K., E.Q., W.F., F.L., J.B., D.-C.W.); Translational Centre for Regenerative Medicine, Leipzig, Germany (A.K., V.B., E.Q., W.F., J.B., D.-C.W.); EVK Bielefeld, Bethel, Neurologische Klinik, Bielefeld, Germany (W.-R.S.); Department of Neurology, University of Münster, Germany (J.M.); and Massachusetts General Hospital and Harvard Medical School, Boston (J.B.). claudia.poesel@izi.fraunhofer.de. 2. From the Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany (C.P., J.S., A.K., E.Q., W.F., F.L., J.B., D.-C.W.); Translational Centre for Regenerative Medicine, Leipzig, Germany (A.K., V.B., E.Q., W.F., J.B., D.-C.W.); EVK Bielefeld, Bethel, Neurologische Klinik, Bielefeld, Germany (W.-R.S.); Department of Neurology, University of Münster, Germany (J.M.); and Massachusetts General Hospital and Harvard Medical School, Boston (J.B.).
Abstract
BACKGROUND AND PURPOSE: We aimed to determine a possible synergistic effect of granulocyte colony-stimulating factor (G-CSF) and bone marrow-derived mononuclear cells (BM MNC) after stroke in spontaneously hypertensive rats. METHODS: Male spontaneously hypertensive rats were subjected to middle cerebral artery occlusion and randomly assigned to daily injection of 50 μg/kg G-CSF for 5 days starting 1 hour after stroke (groups 1, 2, and 3) with additional intravenous transplantation of 1.5×10E7 BM MNC per kilogram at 6 hours (group 2) or 48 hours (group 3) after stroke, or control treatment (group 4). Circulating leukocyte counts and functional deficits, infarct volume, and brain edema were repeatedly assessed in the first week and first month. RESULTS: G-CSF treatment led to a significant neutrophilia, to a reversal of postischemic depression of circulating leukocytes, and to a significantly improved functional recovery without affecting the infarct volume or brain edema. BM MNC cotransplantation was neutral after 6 hours, but reversed the functional effect of G-CSF after 48 hours. Short-term investigation of combined G-CSF and BM MNC treatment at 48 hours indicated splenic accumulation of granulocytes and transplanted cells, accompanied by a significant rise of granulocytes in the circulation and the ischemic brain. CONCLUSIONS: G-CSF improved functional recovery in spontaneously hypertensive rats, but this effect was abolished by cotransplantation of BM MNC after 48 hours. In the spleen, transplanted cells may hinder the clearance of granulocytes that were massively increased by G-CSF. Increased circulation and infiltration of granulocytes into the ischemic brain may be detrimental for stroke outcome.
BACKGROUND AND PURPOSE: We aimed to determine a possible synergistic effect of granulocyte colony-stimulating factor (G-CSF) and bone marrow-derived mononuclear cells (BM MNC) after stroke in spontaneously hypertensiverats. METHODS: Male spontaneously hypertensiverats were subjected to middle cerebral artery occlusion and randomly assigned to daily injection of 50 μg/kg G-CSF for 5 days starting 1 hour after stroke (groups 1, 2, and 3) with additional intravenous transplantation of 1.5×10E7 BM MNC per kilogram at 6 hours (group 2) or 48 hours (group 3) after stroke, or control treatment (group 4). Circulating leukocyte counts and functional deficits, infarct volume, and brain edema were repeatedly assessed in the first week and first month. RESULTS:G-CSF treatment led to a significant neutrophilia, to a reversal of postischemic depression of circulating leukocytes, and to a significantly improved functional recovery without affecting the infarct volume or brain edema. BM MNC cotransplantation was neutral after 6 hours, but reversed the functional effect of G-CSF after 48 hours. Short-term investigation of combined G-CSF and BM MNC treatment at 48 hours indicated splenic accumulation of granulocytes and transplanted cells, accompanied by a significant rise of granulocytes in the circulation and the ischemic brain. CONCLUSIONS:G-CSF improved functional recovery in spontaneously hypertensiverats, but this effect was abolished by cotransplantation of BM MNC after 48 hours. In the spleen, transplanted cells may hinder the clearance of granulocytes that were massively increased by G-CSF. Increased circulation and infiltration of granulocytes into the ischemic brain may be detrimental for stroke outcome.