title: Targeted Differentiation of Regional Ventral Neuroprogenitors and Related Neuronal Subtypes from Human Pluripotent Stem Cells.
abstract: Embryoid body (EB) formation and adherent culture (AD) paradigms are equivalently thought to be applicable for neural specification of human pluripotent stem cells. Here, we report that sonic hedgehog-induced ventral neuroprogenitors under EB conditions are fated to medial ganglionic eminence (MGE), while the AD cells mostly adopt a floor-plate (FP) fate. The EB-MGE later on differentiates into GABA and cholinergic neurons, while the AD-FP favors dopaminergic neuron specification. Distinct developmental, metabolic, and adhesion traits in AD and EB cells may potentially account for their differential patterning potency. Gene targeting combined with small-molecule screening experiments identified that concomitant inhibition of Wnts, STAT3, and p38 pathways (3i) could largely convert FP to MGE under AD conditions. Thus, differentiation paradigms and signaling regulators can be integrated together to specify distinct neuronal subtypes for studying and treating related neurological diseases, such as epilepsy, Alzheimer's disease, and Parkinson's disease.
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China.
authors.forename: Liankai
authors.initials: L
authors.lastname: Chi
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Fan
authors.affiliation: Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Kunshan
authors.initials: K
authors.lastname: Zhang
authors.affiliation: The School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China.
authors.forename: Yujiang
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China.
authors.forename: Xiangjie
authors.initials: X
authors.lastname: Xu
authors.affiliation: The School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
authors.forename: Cizhong
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200092, China.
authors.forename: Siguang
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China; Tongji University Advanced Institute of Translational Medicine, 1239 Siping Road, Shanghai 200092, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China. Electronic address: lianggaoh@126.com.
authors.forename: Liang
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China; Tongji University Advanced Institute of Translational Medicine, 1239 Siping Road, Shanghai 200092, China. Electronic address: lliu@tongji.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Neurosurgery, Shanghai Tenth People's Hospital, Neuroregeneration Key Laboratory of Shanghai Universities, Tongji University School of Medicine, 1239 Siping Road, Shanghai 200092, China; Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai 200092, China; Tongji University Advanced Institute of Translational Medicine, 1239 Siping Road, Shanghai 200092, China; The Collaborative Innovation Center for Brain Science, Tongji University, Shanghai 200092, China. Electronic address: xqzhang@tongji.edu.cn.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
mesh_terms: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D004734:Energy Metabolism; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D059467:Transcriptome; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D050796:STAT3 Transcription Factor; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases
keywords: floor plate; human pluripotent stem cell; medial ganglionic eminence; neural specification; regenerative medicine