Therapeutic Benefit of Bone Marrow Stromal Cells Administered 1 Month after Stroke

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 (3¾10 6 ) 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.

Neurorestorative treatment of stroke: Cell and pharmacological approaches

“…17,18 In addition, delayed treatment of stroke with MSCs at 7 days or at 1 month after stroke onset also increases brain plasticity and improves long-term functional outcome. 17,24,25 …”

Bone marrow-derived mesenchymal stromal cells for the repair of central nervous system injury

“…53 MSCs injected 1 month after stroke demonstrated positive effects in a chronic model with a reduction in scar thickness, increased proliferation of endogenous cells and oligodendrocyte precursor cells, and increased expression of the chemokine stromal cell-derived factor-1 (SCF1) along the ischemic boundary zone and its receptor on the MSCs. 54 Intracarotid transplantation in this model also markedly increased vessel sprouting, synaptophysin expression and the number of oligodendrocyte precursors in the corpus callosum, suggesting axon-myelin remodeling as a mechanism of action. 55 To examine these effects in long term, Chopp found that rats demonstrated significant improvement in neurological outcome at 4 months after transplantation, and showed increased growth-associated protein-43 (GAP43) expression (a marker of axonal growth cones) among reactive astrocytes in the scar boundary and subventricular zone.…”

Neuroprotective Effects of Mesenchymal Stem Cells Derived from Human Embryonic Stem Cells in Transient Focal Cerebral Ischemia in Rats

“…Recombinant tissue plasminogen activator (rtPA), approved by the FDA in the treatment of ischemic stroke, is beneficial for the recovery of blood flow with no effect on the damaged neuronal tissue or vascular endothelium. Recent studies on stem cell therapy in animal models of stroke have revealed promising results (Bliss et al, 2007;Chen et al, 2001a, b;Shen et al, 2007b). Most of these studies used mesenchymal stem cells (MSCs) derived from bone marrow or umbilical cord blood.…”