title: Conversion of monkey fibroblasts to transplantable telencephalic neuroepithelial stem cells.
abstract: Non-human primates provide optimal models for the development of stem cell therapies. Although somatic cells have been converted into neural stem/progenitor cells, it is unclear whether telencephalic neuroepithelial stem cells (NESCs) with stable properties can be generated from fibroblasts in primate. Here we report that a combination of transcription factors (Oct4, Sox2, Klf4) with a new culture medium induces rhesus monkey fibroblasts into NESCs, which can develop into miniature neural tube (NT)-like structures at a cell level. Furthermore, single induced NESCs (iNESCs) can generate later-stage 3D-NTs after grown on matrigel in suspension culture. iNESCs express NT cell markers, have a unique gene expression pattern biasing towards telencephalic patterning, and give rise to cortical neurons. Via transplantation, single iNESCs can extensively survive, regenerate myelinated neuron axons and synapse structures in adult monkey striatum and cortex, and differentiate into cortical neurons. Successful transplantation is closely associated with graft regions and grafted cell identities. The ability to generate defined and transplantable iNESCs from primate fibroblasts under a defined condition with predictable fate choices will facilitate disease modeling and cell therapy.
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China; National Engineering Research Center of Biomedicine and Animal Science, Kunming, Yunnan, 650500, China.
authors.forename: Zongyong
authors.initials: Z
authors.lastname: Ai
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China; Chongqing Key Lab of Forage & Herbivore, College of Animal Science and Technology (CAST), Southwest University, No. 1 Tiansheng Road Beibei, Chongqing, 400715, China; National Engineering Research Center of Biomedicine and Animal Science, Kunming, Yunnan, 650500, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Chongqing Key Lab of Forage & Herbivore, College of Animal Science and Technology (CAST), Southwest University, No. 1 Tiansheng Road Beibei, Chongqing, 400715, China.
authors.forename: Yuemin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
authors.forename: Guoku
authors.initials: G
authors.lastname: Liu
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China; National Engineering Research Center of Biomedicine and Animal Science, Kunming, Yunnan, 650500, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Chongqing Key Lab of Forage & Herbivore, College of Animal Science and Technology (CAST), Southwest University, No. 1 Tiansheng Road Beibei, Chongqing, 400715, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China; National Engineering Research Center of Biomedicine and Animal Science, Kunming, Yunnan, 650500, China.
authors.forename: Shumei
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China; National Engineering Research Center of Biomedicine and Animal Science, Kunming, Yunnan, 650500, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology, No. 157, Jinbi Road, The First People Hospital of Yunnan Province, Kunming, Yunnan, 650032, China. Electronic address: lyh066@gmail.com.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Li
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China; National Engineering Research Center of Biomedicine and Animal Science, Kunming, Yunnan, 650500, China.
authors.forename: Weizhi
authors.initials: W
authors.lastname: Ji
authors.affiliation: Yunnan Key Lab of Primate Biomedicine Research; Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, Yunnan, 650500, China; National Engineering Research Center of Biomedicine and Animal Science, Kunming, Yunnan, 650500, China. Electronic address: litq@kbimed.com.
authors.forename: Tianqing
authors.initials: T
authors.lastname: Li
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000187:drug effects; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003342:Corpus Striatum / Q000166:cytology; D003470:Culture Media / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000502:physiology; D016086:Lentivirus / Q000235:genetics; D008253:Macaca mulatta; D008297:Male; D009413:Nerve Fibers, Myelinated / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology* / Q000637:transplantation; D054259:Neural Tube / Q000166:cytology; D046569:Neuroepithelial Cells / Q000166:cytology* / Q000637:transplantation; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000502:physiology; D009928:Organ Specificity; D017397:Prefrontal Cortex / Q000166:cytology; D012190:Retroviridae / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000502:physiology; D013687:Telencephalon; D059467:Transcriptome; D014161:Transduction, Genetic
chemical_list: D003470:Culture Media; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D050814:Octamer Transcription Factor-3; D055748:SOXB1 Transcription Factors
keywords: Cortical neuron; Monkey fibroblasts; Neural regeneration in vivo; Neural tubes; Telencephalic neuroepithelial stem cells; Transdifferentiation