Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo

Ira Espuny-Camacho; Kimmo A Michelsen; David Gall; Daniele Linaro; Anja Hasche; Jérôme Bonnefont; Camilia Bali; David Orduz; Angéline Bilheu; Adèle Herpoel; Nelle Lambert; Nicolas Gaspard; Sophie Péron; Serge N Schiffmann; Michele Giugliano; Afsaneh Gaillard; Pierre Vanderhaeghen

doi:10.1016/j.neuron.2012.12.011

Pyramidal neurons derived from human pluripotent stem cells integrate efficiently into mouse brain circuits in vivo

Neuron. 2013 Feb 6;77(3):440-56. doi: 10.1016/j.neuron.2012.12.011.

Authors

Ira Espuny-Camacho¹, Kimmo A Michelsen, David Gall, Daniele Linaro, Anja Hasche, Jérôme Bonnefont, Camilia Bali, David Orduz, Angéline Bilheu, Adèle Herpoel, Nelle Lambert, Nicolas Gaspard, Sophie Péron, Serge N Schiffmann, Michele Giugliano, Afsaneh Gaillard, Pierre Vanderhaeghen

Affiliation

¹ 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.

PMID: 23395372
DOI: 10.1016/j.neuron.2012.12.011

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.

Publication types

Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
Age Factors
Animals
Axons / physiology
Brain / cytology*
Bromodeoxyuridine
Calcium / metabolism
Cell Differentiation
Cell Transplantation
Cells, Cultured
Dendrites / physiology
Embryonic Stem Cells / cytology*
Evoked Potentials / physiology
Excitatory Amino Acid Antagonists / pharmacology
Female
Fetus
Fluorescent Dyes / metabolism
Gene Expression Profiling
Gene Expression Regulation, Developmental / physiology
Green Fluorescent Proteins / genetics
Humans
In Vitro Techniques
Mice
Microscopy, Electron, Transmission
Microtubule-Associated Proteins / metabolism
Nerve Net / physiology*
Nerve Net / ultrastructure
Nerve Tissue Proteins / metabolism
Oligonucleotide Array Sequence Analysis
Patch-Clamp Techniques
Pluripotent Stem Cells / physiology*
Pregnancy
Pyramidal Cells / cytology
Pyramidal Cells / physiology*
RNA, Messenger / metabolism
Synapses / metabolism
Synapses / ultrastructure
Synaptic Potentials / physiology
Transcription Factors / genetics
Transcription Factors / metabolism
Transduction, Genetic
Tyrosine 3-Monooxygenase / metabolism
Valine / analogs & derivatives
Valine / pharmacology
Vesicular Glutamate Transport Protein 1 / metabolism

Substances

Excitatory Amino Acid Antagonists
Fluorescent Dyes
Microtubule-Associated Proteins
Mtap2 protein, mouse
Nerve Tissue Proteins
RNA, Messenger
Transcription Factors
Vesicular Glutamate Transport Protein 1
Green Fluorescent Proteins
6-Cyano-7-nitroquinoxaline-2,3-dione
2-amino-5-phosphopentanoic acid
Tyrosine 3-Monooxygenase
Bromodeoxyuridine
Valine
Calcium