Intrastriatal Transplantation of Bone Marrow Nonhematopoietic Cells Improves Functional Recovery After Stroke in Adult Mice

Li, Yang; Chopp, Michael; Chen, Jieli; Wang, Lei; Gautam, Subhash C.; Xu, Yong; Zhang, Zhenggang

doi:10.1097/00004647-200009000-00006

Cited by 466 publications

(304 citation statements)

References 57 publications

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“…We also found on day 14 that the MSC-only treated group could significantly reduce the infarction volume under the superacute treatment compared with the PBS-treated group, but not under the acute treatment. This was the same as the Chopp's group had reported, that transplanted MSCs to the transient MCAO model 24 h after ischemia occurred had improved neurological function recovery, but not significantly decreased infarction area Li et al, 2000Li et al, , 2001, while our data of the superacute treatment showed the contrast result. We thought that it might have been caused by the different therapeutic time window.…”

Section: Discussionsupporting

confidence: 90%

Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and ex vivo HGF Gene Transfer with HSV-1 Vector

Zhao

Nonoguchi

Ikeda

et al. 2006

J Cereb Blood Flow Metab

123

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Occlusive cerebrovascular disease leads to brain ischemia that causes neurological deficits. Here we introduce a new strategy combining mesenchymal stromal cells (MSCs) and ex vivo hepatocyte growth factor (HGF) gene transferring with a multimutated herpes simplex virus type-1 vector in a rat transient middle cerebral artery occlusion (MCAO) model. Gene-transferred MSCs were intracerebrally transplanted into the rats' ischemic brains at 2 h (superacute) or 24 h (acute) after MCAO. Behavioral tests showed significant improvement of neurological deficits in the HGF-transferred MSCs (MSC-HGF)-treated group compared with the phosphatebuffered saline (PBS)-treated and MSCs-only-treated group. The significant difference of infarction areas on day 3 was detected only between the MSC-HGF group and the PBS group with the superacute treatment, but was detected among each group on day 14 with both transplantations. After the superacute transplantation, we detected abundant expression of HGF protein in the ischemic brain of the MSC-HGF group compared with others on day 1 after treatment, and it was maintained for at least 2 weeks. Furthermore, we determined that the increased expression of HGF was derived from the transferred HGF gene in gene-modified MSCs. The percentage of apoptosis-positive cells in the ischemic boundary zone (IBZ) was significantly decreased, while that of remaining neurons in the cortex of the IBZ was significantly increased in the MSC-HGF group compared with others. The present study shows that combined therapy is more therapeutically efficient than MSC cell therapy alone, and it may extend the therapeutic time window from superacute to acute phase.

show abstract

Section: Discussionsupporting

confidence: 90%

Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and ex vivo HGF Gene Transfer with HSV-1 Vector

Zhao

Nonoguchi

Ikeda

et al. 2006

J Cereb Blood Flow Metab

123

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show abstract

“…Effective therapeutics for the rehabilitation of stroke survivors have yet to be developed. Recently Chopp and coworkers reported that rodent bone marrow cells grafted into the ischemic rat brain resulted in functional improvement (32). In this study, however, bone marrow cells were not purified to isolate stem cells.…”

Section: Introductionmentioning

confidence: 85%

Human Bone Marrow Stem Cells Exhibit Neural Phenotypes and Ameliorate Neurological Deficits after Grafting into the Ischemic Brain of Rats

Zhao

Duan

Reyes

et al. 2002

Experimental Neurology

755

466

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There is now evidence to suggest that bone marrow mesenchymal stem cells (MSCs) not only differentiate into mesodermal cells, but can also adopt the fate of endodermal and ectodermal cell types. In this study, we addressed the hypotheses that human MSCs can differentiate into neural cells when implanted in the brain and restore sensorimotor function after experimental stroke. Purified human MSCs were grafted into the cortex surrounding the area of infarction 1 week after cortical brain ischemia in rats. Two and 6 weeks after transplantation animals were assessed for sensorimotor function and then sacrificed for histological examination. Ischemic rats that received human MSCs exhibited significantly improved functional performance in limb placement test. Histological analyses revealed that transplanted human MSCs expressed markers for astrocytes (GFAP ؉ ), oligodendroglia (GalC ؉ ), and neurons (␤III ؉ , NF160 ؉ , NF200 ؉ , hNSE ؉ , and hNF70 ؉ ). The morphological features of the grafted cells, however, were spherical in nature with few processes. Therefore, it is unlikely that the functional recovery observed by the ischemic rats with human MSC grafts was mediated by the integration of new "neuronal" cells into the circuitry of the host brain. The observed functional improvement might have been mediated by proteins secreted by transplanted hMSCs, which could have upregulated host brain plasticity in response to experimental stroke.

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“…Modified neurologic severity scores (mNSS): Neurologic function was graded on a scale of 0 to 14 (normal score 0; maximal deficit score 14, see Table 1; Li et al, 2000). mNSS is a composite of motor, reflex and balance tests.…”

Section: Behavioral Testsmentioning

confidence: 99%

Atorvastatin Induction of VEGF and BDNF Promotes Brain Plasticity after Stroke in Mice

Chen¹,

Zhang²,

Jiang³

et al. 2005

J Cereb Blood Flow Metab

Self Cite

401

337

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Molecular mechanisms underlying the role of statins in the induction of brain plasticity and subsequent improvement of neurologic outcome after treatment of stroke have not been adequately investigated. Here, we use both in vivo and in vitro studies to investigate the potential roles of two prominent factors, vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), in mediating brain plasticity after treatment of stroke with atorvastatin. Treatment of stroke in adult mice with atorvastatin daily for 14 days, starting at 24 hours after MCAO, shows significant improvement in functional recovery compared with control animals. Atorvastatin increases VEGF, VEGFR2 and BDNF expression in the ischemic border. Numbers of migrating neurons, developmental neurons and synaptophysin-positive cells as well as indices of angiogenesis were significantly increased in the atorvastatin treatment group, compared with controls. In addition, atorvastatin significantly increased brain subventricular zone (SVZ) explant cell migration in vitro. Anti-BDNF antibody significantly inhibited atorvastatin-induced SVZ explant cell migration, indicating a prominent role for BDNF in progenitor cell migration. Mouse brain endothelial cell culture expression of BDNF and VEGFR2 was significantly increased in atorvastatin-treated cells compared with control cells. Inhibition of VEGFR2 significantly decreased expression of BDNF in brain endothelial cells. These data indicate that atorvastatin promotes angiogenesis, brain plasticity and enhances functional recovery after stroke. In addition, VEGF, VEGFR2 and BDNF likely contribute to these restorative processes.

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Intrastriatal Transplantation of Bone Marrow Nonhematopoietic Cells Improves Functional Recovery After Stroke in Adult Mice

Cited by 466 publications

References 57 publications

Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and ex vivo HGF Gene Transfer with HSV-1 Vector

Novel Therapeutic Strategy for Stroke in Rats by Bone Marrow Stromal Cells and ex vivo HGF Gene Transfer with HSV-1 Vector

Human Bone Marrow Stem Cells Exhibit Neural Phenotypes and Ameliorate Neurological Deficits after Grafting into the Ischemic Brain of Rats

Atorvastatin Induction of VEGF and BDNF Promotes Brain Plasticity after Stroke in Mice

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