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Many physiological and molecular mechanisms involving <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content> therapy\u2010related neuroprotection have been identified.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A review is presented of articles that pertain to <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content> therapy and diverse brain injuries including stroke, neural trauma, and heat stroke, which were identified using an electronic search (e.g., PubMed), emphasize mechanisms of <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content> therapy\u2010related neuroprotection. We aim to discuss neuroprotective mechanisms that underlie the beneficial effects of <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>s in treating stroke, neural trauma, and heatstroke.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content> therapy is promising as a means of augmenting brain repair. Cell incorporation into the injured tissue is not a prerequisite for the beneficial effects exerted by <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>s. Paracrine signaling is believed to be the most important mediator of <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content> therapy in brain injury. The multiple mechanisms of action of <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>s include enhanced angiogenesis and neurogenesis, immunomodulation, and anti\u2010inflammatory effects. Microglia are the first source of the inflammatory cascade during brain injury. Cytokines, including tumor necrosis factor\u2010\u03b1, interleukin\u20101\u03b2, and interleukin\u20106, are significantly produced by microglia in the brain after experimental brain injury. The proinflammatory M1 phenotype of microglia is associated with tissue destruction, whereas the anti\u2010inflammatory M2 phenotype of microglia facilitates repair and regeneration. <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content> therapy may improve outcomes of ischemic stroke, neural trauma, and heatstroke by inhibiting the activity of M1 phenotype of microglia but augmenting the activity of M2 phenotype of microglia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This review offers a testable platform for targeting microglial\u2010mediated cytokines in clinical trials based upon the rational design of <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content> therapy in the future. <jats:styled-content style=\"fixed-case\">MSC<\/jats:styled-content>s that are derived from the placenta provide a great choice for stem cell therapy. Although targeting the microglial activation is an important approach to reduce the burden of the injury, it is not the only one. This review focuses on this specific aspect.<\/jats:p><\/jats:sec>","DOI":"10.1002\/brb3.526","type":"journal-article","created":{"date-parts":[[2016,8,3]],"date-time":"2016-08-03T05:07:04Z","timestamp":1470200824000},"source":"Crossref","is-referenced-by-count":94,"title":["Mesenchymal stem cell\u2010based treatments for stroke, neural trauma, and heat stroke"],"prefix":"10.1002","volume":"6","author":[{"given":"Yogi Chang\u2010Yo","family":"Hsuan","sequence":"first","affiliation":[{"name":"Meridigen Biotech CO., Ltd.  Neihu Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng\u2010Hsien","family":"Lin","sequence":"additional","affiliation":[{"name":"Meridigen Biotech CO., Ltd.  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