title: Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo.
abstract: The study of human cortical development has major implications for brain evolution and diseases but has remained elusive due to paucity of experimental models. Here we found that human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), cultured without added morphogens, recapitulate corticogenesis leading to the sequential generation of functional pyramidal neurons of all six layer identities. After transplantation into mouse neonatal brain, human ESC-derived cortical neurons integrated robustly and established specific axonal projections and dendritic patterns corresponding to native cortical neurons. The differentiation and connectivity of the transplanted human cortical neurons complexified progressively over several months in vivo, culminating in the establishment of functional synapses with the host circuitry. Our data demonstrate that human cortical neurons generated in vitro from ESC/iPSC can develop complex hodological properties characteristic of the cerebral cortex in vivo, thereby offering unprecedented opportunities for the modeling of human cortex diseases and brain repair.
authors: Université Libre de Bruxelles (U.L.B.), Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), and ULB Neuroscience Institute (UNI), B-1070 Brussels, Belgium.
authors: Ira
authors: I
authors: Espuny-Camacho
authors: Kimmo A
authors: KA
authors: Michelsen
authors: David
authors: D
authors: Gall
authors: Daniele
authors: D
authors: Linaro
authors: Anja
authors: A
authors: Hasche
authors: Jérôme
authors: J
authors: Bonnefont
authors: Camilia
authors: C
authors: Bali
authors: David
authors: D
authors: Orduz
authors: Angéline
authors: A
authors: Bilheu
authors: Adèle
authors: A
authors: Herpoel
authors: Nelle
authors: N
authors: Lambert
authors: Nicolas
authors: N
authors: Gaspard
authors: Sophie
authors: S
authors: Péron
authors: Serge N
authors: SN
authors: Schiffmann
authors: Michele
authors: M
authors: Giugliano
authors: Afsaneh
authors: A
authors: Gaillard
authors: Pierre
authors: P
authors: Vanderhaeghen
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D001369:Axons / Q000502:physiology; D001921:Brain / Q000166:cytology*; D001973:Bromodeoxyuridine; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D017690:Cell Transplantation; D002478:Cells, Cultured; D003712:Dendrites / Q000502:physiology; D053595:Embryonic Stem Cells / Q000166:cytology*; D005071:Evoked Potentials / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005333:Fetus; D005456:Fluorescent Dyes / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009415:Nerve Net / Q000502:physiology* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018408:Patch-Clamp Techniques; D039904:Pluripotent Stem Cells / Q000502:physiology*; D011247:Pregnancy; D017966:Pyramidal Cells / Q000166:cytology / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000648:ultrastructure; D055366:Synaptic Potentials / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D005456:Fluorescent Dyes; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D050598:Vesicular Glutamate Transport Protein 1; D049452:Green Fluorescent Proteins; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D014446:Tyrosine 3-Monooxygenase; D001973:Bromodeoxyuridine; D014633:Valine; D002118:Calcium