title: In Situ Pluripotency Factor Expression Promotes Functional Recovery From Cerebral Ischemia.
abstract: Recovery from ischemic tissue injury can be promoted by cell proliferation and neovascularization. Transient expression of four pluripotency factors (Pou5f1, Sox2, Myc, and Klf4) has been used to convert cell types but never been tested as a means to promote functional recovery from ischemic injury. Here we aimed to determine whether transient in situ pluripotency factor expression can improve neurobehavioral function. Cerebral ischemia was induced by transient bilateral common carotid artery occlusion, after which the four pluripotency factors were expressed through either doxycycline administration into the lateral ventricle in transgenic mice in which the four factors are expressed in a doxycycline-inducible manner. Histologic evaluation showed that this transient expression induced the proliferative generation of astrocytes and/or neural progenitors, but not neurons or glial scar, and increased neovascularization with upregulation of angiogenic factors. Furthermore, in vivo pluripotency factor expression caused neuroprotective effects such as increased numbers of mature neurons and levels of synaptic markers in the striatum. Dysplasia or tumor development was not observed. Importantly, neurobehavioral evaluations such as rotarod and ladder walking tests showed that the expression of the four factors dramatically promoted functional restoration from ischemic injury. These results provide a basis for novel therapeutic modality development for cerebral ischemia.
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.|Department of Rehabilitation Medicine, Hallym University Burn Institute, Burn Center, Hangang Sacred Heart Hospital, Seoul, Korea.
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Seo
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Min-Young
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.
authors.forename: Ji Hea
authors.initials: JH
authors.lastname: Yu
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Myung-Sun
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.|Graduate School of Biomedical Science and Engineering/College of Medicine, Hanyang University, Seoul, Korea.
authors.forename: Myungjae
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Rehabilitation Medicine, Hallym University Burn Institute, Burn Center, Hangang Sacred Heart Hospital, Seoul, Korea.
authors.forename: Cheong Hoon
authors.initials: CH
authors.lastname: Seo
authors.affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.|Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.|Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Hyongbum Henry
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department and Research Institute of Rehabilitation Medicine, Yonsei University College of Medicine, Seoul, Korea.|Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea.|Rehabilitation Institute of Neuromuscular Disease, Yonsei University College of Medicine, Seoul, Korea.|Yonsei Stem Cell Research Center, Avison Biomedical Research Center, Seoul, Korea.
authors.forename: Sung-Rae
authors.initials: SR
authors.lastname: Cho
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002545:Brain Ischemia / Q000235:genetics* / Q000503:physiopathology*; D002452:Cell Count; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D016259:Genes, myc; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D020547:Lateral Ventricles / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D020127:Recovery of Function / Q000235:genetics*; D055748:SOXB1 Transcription Factors / Q000235:genetics
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors