Timing and Dose Regimens of Marrow Mesenchymal Stem Cell Transplantation Affect the Outcomes and Neuroinflammatory Response After Ischemic Stroke

• Published in: CNS neuroscience & therapeutics 2014-04, Vol.20 (4), p.317-326
• Main Authors: Wang, Liu‐Qing, Lin, Zhen‐Zhen, Zhang, Hong‐Xia, Shao, Bei, Xiao, Li, Jiang, Hui‐Gang, Zhuge, Qi‐Chuan, Xie, Luo‐Kun, Wang, Brian, Su, Dong‐Ming, Jin, Kun‐Lin
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biological and medical sciences; Blood. Blood coagulation. Reticuloendothelial system; Brain - immunology; Brain - pathology; Brain - surgery; Brain Ischemia - immunology; Brain Ischemia - pathology; Brain Ischemia - surgery; Cells, Cultured; Cytokines - metabolism; Development. Senescence. Regeneration. Transplantation; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Humans; Infarction, Middle Cerebral Artery - immunology; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - surgery; Injury; Ischemia; Isolated neuron and nerve. Neuroglia; Macrophages - physiology; Marrow mesenchymal stem cells; Medical sciences; Mesenchymal Stem Cell Transplantation - methods; Microglia - physiology; Middle Aged; Neuroinflammation; Neurology; Original; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Recovery of Function; Stroke; Stroke - immunology; Stroke - pathology; Stroke - surgery; T-Lymphocytes - physiology; Time Factors; Transplantation; Treatment Outcome; Vascular diseases and vascular malformations of the nervous system; Vertebrates: nervous system and sense organs
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12216

Summary Aims Intravenous transplantation of bone marrow mesenchymal stem cells (BMSCs) had been documented to improve functional outcome after ischemic stroke. However, the timing and appropriate cell number of transplantation to achieve better outcome after an episode of stroke remain further to be optimized. Methods To determine the optimal conditions, we transplanted different concentrations of BMSCs at different time points in a rat model of ischemic stroke. Infarction volume and neurological behavioral tests were performed after ischemia. Results We found that transplantation of BMSCs at 3 and 24 h, but not 7 days after focal ischemia, significantly reduced the lesion volume and improved motor deficits. We also found that transplanted cells at 1 × 106 to 107, but not at 1 × 104 to 105, significantly improved functional outcome after stroke. In addition to inhibiting macrophages/microglia activation in the ischemic brain, BMSC transplantation profoundly reduced infiltration of gamma delta T (γδT) cells, which are detrimental to the ischemic brain, and significantly increased regulatory T cells (Tregs), along with altered Treg‐associated cytokines in the ischemic brain. Conclusions Our data suggest that timing and cell dose of transplantation determine the therapeutic effects after focal ischemia by modulating poststroke neuroinflammation.