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Induced pluripotent stem cells (iPSCs) have the potential to generate all cell types <jats:italic>in vitro<\/jats:italic> and can be generated from a stroke patient. Therefore, iPSCs are attractive donor sources of genetically identical \u201cpatient-specific\u201d cells to hold promise in therapy for stroke. In the present study, we established a four-stage culture system by using serum-free medium and retinoic acid (RA) to differentiate iPSCs into neural stem cells (NSCs) effectively and stably. Our hypothesis was that iPSC-derived NSCs would survive, migrate, and differentiate <jats:italic>in vivo<\/jats:italic>, and improve neurologic function after transplantation into the brains of rats with ischemic stroke.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>Human iPSCs (iPS-S-01) and human ESCs (HuES17) were used to differentiate into NSCs by using our four-stage culture system. iPSCs and differentiated NSCs were characterized by immunocytochemistry staining and reverse transcription-polymerase chain reaction (RT-PCR) analysis. After establishment of focal cerebral ischemia with occlusion of the middle cerebral artery (MCA) and cell transplantation, animals were killed at 1\u00a0week and 2\u00a0weeks to analyze survival, migration, and differentiation of implanted cells in brain tissue. Animal behavior was evaluated via rope grabbing, beam walking, and Morris water maze tests.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>iPSCs were efficiently induced into NSCs by using a newly established four-stage induction system <jats:italic>in vitro<\/jats:italic>. iPSCs expressed pluripotency-associated genes <jats:italic>Oct4<\/jats:italic>, <jats:italic>Sox2<\/jats:italic>, and <jats:italic>Nanog<\/jats:italic> before NSC differentiation. The iPSC-derived NSCs spontaneously differentiated into neurons and astrocytes, which highly express \u03b2-tubulin and glial fibrillary acidic protein (GFAP), respectively. On transplantation into the striatum, CM-DiI labeled iPSC-derived NSCs were found to migrate into the ischemia area at 1\u00a0week and 2\u00a0weeks, and animal-function recovery was significantly improved in comparison with control groups at 3\u00a0weeks.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>The four-stage induction system is stable and effective to culture, differentiate, and induce iPSCs to NSCs by using serum-free medium combined with retinoic acid (RA). Implanted iPSC-derived NSCs were able to survive, migrate into the ischemic brain area to differentiate into mature neural cells, and seem to have potential to restore lost neurologic function from damage due to stroke in a rat model.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/scrt224","type":"journal-article","created":{"date-parts":[[2013,6,14]],"date-time":"2013-06-14T17:27:22Z","timestamp":1371230842000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":135,"title":["Human induced pluripotent stem cell-derived neural stem cells survive, migrate, differentiate, and improve neurologic function in a rat model of middle cerebral artery occlusion"],"prefix":"10.1186","volume":"4","author":[{"given":"Ting","family":"Yuan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nian-Hua","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan-Lei","family":"Lou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai-Jun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Feng","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2013,6,14]]},"reference":[{"key":"222_CR1","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1515\/revneuro-2012-0042","volume":"23","author":"Y Zhu","year":"2012","unstructured":"Zhu Y, Wan S, Zhan RY: Inducible pluripotent stem cells for the treatment of ischemic stroke: current status and problems. 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