1. ¹Department of Neurology, Henry Ford Health Sciences Center, Henry Ford Hospital, Detroit, Michigan, USA
2. ²Department of Biostatistics and Research Epidemiology, Henry Ford Health Sciences Center, Detroit, Michigan, USA
3. ³Cognate Therapeutics Inc., Baltimore, Maryland, USA
4. ⁴Theradigm Inc., Baltimore, Maryland, USA
5. ⁵Department of Physics, Oakland University, Rochester, Michigan, USA

Correspondence: Dr M Chopp, Department of Neurology, Henry Ford Health Sciences Center, Henry Ford Hospital, E&R 3056, 2799 West Grand Boulevard, Detroit, Michigan 48202, USA. E-mail: chopp@neuro.hfh.edu

Received 30 November 2005; Revised 23 February 2006; Accepted 26 February 2006; Published online 5 April 2006.

Abstract

Bone marrow stromal cells (BMSCs) facilitate functional recovery in rats after stroke when administered acutely (1 day) or subacutely (7 days). In this study, we postponed the time of cell transplantation to 1 month after stroke. Female retired breeder rats were subjected to 2 h of middle cerebral artery occlusion (MCAo). Male BMSCs (3 10⁶) or phosphate-buffered saline were administered intravenously, and the animals were killed 3 months later. An additional population of nontreated rats was killed at 1 month after MCAo. Significant recovery of behavior was found in BMSC-treated rats beginning at 1 month after cell injection in the modified neurologic severity score test and the adhesive-removal test compared with control animals (P<0.05). In situ hybridization showed that BMSCs survived and preferentially localized to the ipsilateral hemisphere. Double staining revealed that approximately 13% and 6% Y-chromosome-positive cells expressed the astrocyte marker, glial fibrillary acidic protein, and the neuronal marker, microtubule-associated protein-2, respectively. In addition, BMSC treatment reduced scar thickness, and increased the number of proliferating cells and oligodendrocyte precursor cells along the subventricular zone in the ipsilateral hemisphere. Expression of the chemokine stromal-cell-derived factor-1 (SDF-1) was significantly increased along the ischemic boundary zone compared with the corresponding areas in the contralateral hemisphere at 1 month and 4 months (P<0.01) after stroke. The SDF-1 receptor, CXC-chemokine receptor-4 (CXCR4), was expressed in BMSCs both in vitro and in vivo. Our data show that the time window of BMSC therapy is at least 1 month after stroke; the interaction of SDF-1/CXCR4 may contribute to the trafficking of transplanted BMSCs.