| Backround and ObjectiveCerebravascular disease (CVD) is one of clinical common diseases, which rank to the 3rd leading cause of death to human being and the 1st cause of death lead by all vascular diseases.70% of cerebravascular diseases are ischemic and even up to 85% in USA and Eeurop country. Up to now, there is no better method to treat such patients except thrombolytic therapy in the acute period. BMSCs have newly developed to be a promising method on the treatment of ischemic cerebral stroke.The encouraged results of pre-clinical reserch promote BMSCs based treatment strategy to translate to clinic. The Phase I and II clinical trials approved by FDA with BMSC cells transplanted via vein for brain ischemia did report some adverse,which approved safty and efficiency of the method.However there still exist a lot of controversial issues about BMSCs therapy for stroke in the pre-clinical research,such as patients selection,theraputic windown.route of delivery. Bone marrow mesenchymal stem cells (BMSCs) are multipotent and represent one group of non-hematopoietic stem cells in the marrow, which can differentiate into multiple lineages. BMSCs become one of the most promising stem cells in the field of regenerative medicine for their advantage of easy accessibility and lower immogenecity. The best route of stem cell delivery associate to clinical treatment closely,so in present study we designed a series experiments to imitate clinical route and explored the effects and the machenism of BMSCs transplantation to cerebral ischemia in order to supply the experimental data for clinical application.MethodsBased on rats MCAO and reperfusion model, we have studied dynamicly the relative aspects of BMSCs transplantation by different routes. The study includes two parts:1. Study the survival time, migration and differentiation of BMSCs in vivo deliveried by different routs. Assess the rats's behaviors depend on series behavioral tests at different time points. Assess the relationship between efficiency and BMSCs delivery routes and find the most efficient routes.2. Study the promotion angiogenesis function of BMSCs deliveried by transcarotid route promote based on function tests,morphology,metabology.Results1.hBMSCs-induced therapeutic benefits following stroke have strong relationship to cell dose in brain and distribution pattern.2.Our observations showed that delivery routes dramatically affected the migration and distribution of grafted cells and treatment efficiency. Transvessel rout takes advantage of space distribution pattern,while brain sterotaxy takes advantage of dose in infarction territory and penumbra.3.Compare the teatment efficiency of hBMSCs (1×106) delivered by different routes during acute phase(24h after ischemia):A group is superior to B,C,D,E group; C group is superior to B,D,E group;B group is superior to D.E group; During early phase,rats function improvement can be observed in E group,however there is no significant difference with F group.4.So many hBMSCs survived after 2 weeks of transplantation via atery route. However, the number of hBMSC decreased at the 3rd week after transplantation and few cells could be detected at 1 month. Our result also showed the hBMSCs can migrate to the border of ischemia during the first 2 weeks.5.Evidence supported the differentiation of vascular endothelial cell derived from hBMSC.6. hBMSCs increase VEGF secretion and angiogenesis in the border territory of iinfarction,then the blood perfusion and metablisim level improve. ConclusionOur results showed that BMSCs transplanted into brain cortex via different rout can improve neurofunctional recovery after cerebral ischemia. The transplanted stem cells can survive and migrate towards the lesion during certain period, and evidence support that hBMSCs can differentiate into vascular endothilial cell in viovo,at same time the hBMSCs express some markers association to neuroplasticity. Delivery routes dramatically affected the migration and distribution of grafted cells and treatment efficiency.All the results support that intracarotid delivery routes has an advantage over other routs,while the route of lumbar subarachnoid is not as good as we expected.
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