Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses.
Efforts to study the development and function of the human cerebral cortex in health and disease have been limited by the availability of model systems. Extrapolating from our understanding of rodent cortical development, we have developed a robust, multistep process for human cortical development from pluripotent stem cells: directed differentiation of human embryonic stem (ES) and induced pluripotent stem (iPS) cells to cortical stem and progenitor cells, followed by an extended period of cortical neurogenesis, neuronal terminal differentiation to acquire mature electrophysiological properties, and functional excitatory synaptic network formation. We found that induction of cortical neuroepithelial stem cells from human ES cells and human iPS cells was dependent on retinoid signaling. Furthermore, human ES cell and iPS cell differentiation to cerebral cortex recapitulated in vivo development to generate all classes of cortical projection neurons in a fixed temporal order. This system enables functional studies of human cerebral cortex development and the generation of individual-specific cortical networks ex vivo for disease modeling and therapeutic purposes.
Gurdon Institute, University of Cambridge, Cambridge, UK.
Yichen
Y
Shi
Peter
P
Kirwan
James
J
Smith
Hugh P C
HP
Robinson
Frederick J
FJ
Livesey
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology*; D000076122:Disks Large Homolog 4 Protein; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012333:RNA, Messenger; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C481395:4-aminopiperidine; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010880:Piperidines; D026902:Potassium Channel Blockers; D012333:RNA, Messenger; D012176:Retinoids; D026941:Sodium Channel Blockers; D014157:Transcription Factors; C485548:UNC13B protein, human; D018698:Glutamic Acid; D013779:Tetrodotoxin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione