Stem cells in neurodevelopment
Human development and associated diseases with in vitro models (embryoids, organoids…)
Our lab is studying the molecular and cellular basis of human development in health and disease. To approach this question we use human pluripotent stem cell differentiation into organoids or specific cell types coupled to transcriptomic, optogenetic and live imaging approaches
We seek to decode the principles controlling the specification and organization of neural diversity and how genetic mutations perturb these events to cause disorders. To approach these questions, we are creating in vitro models of human embryogenesis (embryoids, organoids and directed differentiation) based on the differentiation human induced pluripotent stem cells. These models are not only revolutionizing the way we address the mechanisms controlling the formation of organs and specific cell types, but also open avenues to produce defined cell populations or tissues (cell and tissue engineering) to study disease mechanims, for cell therapy strategies (transplantation) or drug screening.
Human development / cell and tissue engineering.
1) Using targeted differentiation of human pluripotent stem cells toward specific neuronal subtypes, we investigate the signal transduction pathways and genetic networks that ensure the formation of distinct locomotor neural circuits along the body axis. (Projects of Célia Vaslin and Rémi Robert, see also Nedelec, Martinez-Arias, Cur. Op. Neuro, 2021). Building on our previous work in which we invented a new way to investigate cell fate control using in vitro differentiation of human pluripotent stem cells (Maury et al. Nature Biotechnology, 2015), we have recently discovered mechanisms regulating HOX gene expression resulting in the first efficient methods to generate distinct motor neuron subtypes differentially impacted in motor neuron diseases (Mouilleau, Vaslin et al, Development, 2021). Rémi Robert, a graduate student in the group, continue to explore the links between extrinsic cues and the HOX timer using transcriptomic and live imaging of signaling reporters. Collaboration : Benoit Sorre (Institut Curie, Paris), Vanessa Ribes (IJM, Paris), Esteban Mazzoni (NYU, New York)
2) Using a new multi-lineage embryoid model we have recently regenerated , Simona Gribaudo is studying the coupling between the morphogenesis of the neural tube and the spatial allocation of specific neuronal circuits. We combine live imaging, single cell and spatial transcriptomic to approach this question.
Collaboration Alexander van Oudenaarden lab (Hubrecht institute, Utrecht, NL) and Xavier Morin lab (ENS, Paris). ANR funded project
Basis of neurodevelopmental and neurodegenrative disorders
These in vitro models provide access to human tissues or cell types affected in pathologies. We use patient-derived induced pluripotent stem cells to study the basis of motor neuron diseases, a heterogeneous group of incurable and often fatal diseases. In particular, we are studying infantile spinal muscular atrophies (SMAs) and juvenile ALS which, although caused by mutations in ubiquitously expressed genes, are characterized by defects in the formation or survival of particular populations of motor neurons while others are preserved. Deciphering the basis of the vulnerability or the resistance of these different types of motor neurons should open new therapeutic avenues
1) Maeliss Calon, a graduate student cosupervised with Alexandre Baffet is investigatin the Deregulation of axonal transport and motor neuron subtype differential vulnerability in distal spinal muscular atrophies.
Collaboration with the Baffet lab (Curie), N. Bahi-Buisson (Imagine) and A. Rossor (UCL), C. Villard (IPGG, Paris). ANR and AFM funded program.
2) Marta Giannini, a post-doc, is studying the Molecular and cellular basis of a juvenile form of amyotrophic lateral sclerosis caused by Senataxin mutations.
Collaboration with Odil Porrua, IGGM, Montpellier.
- Human induced pluripotent stem cell (iPS)
- Live imaging
Team leader : Stéphane NEDELEC CR1 INSERM
- Simona Gribaudo, Research engineer, Sorbonne Université
- Rémi Robert, PhD student (Cosupervised with J. van Helden, ATGC, Marseille)
- Maeliss Calon, PhD student (Cosupervised with A. Baffet, Curie Institute)
- Marta Giannini, Post doctoral scientist (between O. Porrua and Nedelec labs)
- Ribes lab , IJM, Paris
- van Oudenaarden lab, Hubrecht, Utrecht
- Baffet lab, Curie Institute, Paris
- Bahi-Buisson lab, Imagine Institute, Paris
- Livet lab, institut de la vision, Paris
- Morin lab, ENS, Paris
- Rossor lab, UCL, London
- Mazzoni lab, NYU, New York,
- Wichterle lab, Columbia University, New York
- Coppey lab, Curie institute, Paris
- Sorre lab, Curie institute, Paris
- Villard lab, IPGG, Paris
- Porrua-Fuerte lab, IGMM, Montpellier
- ATIP/Avenir program – Inserm
- Association Francaise contre les Myopathies (AFM)
- Agence Nationale de la Recherche (ANR)
- Fondation pour la Recherche Médicale (FRM)
- Fondation maladies rares
Most Recent Publications
Dynamic extrinsic pacing of the HOX clock in human axial progenitors controls motor neuron subtype specification
Mouilleau V, Vaslin C, Robert R, Gribaudo S, Nicolas N, Jarrige M, Terray A, Lesueur L, W Mathis M, Croft G, Daynac M, Rouiller-Fabre V, Wichterle H, Ribes V, Martinat C, Nedelec S
Development (2021) 148: dev194514
In vitro models of spinal motor circuit’s development in mammals: achievements and challenges.
Nedelec S, Martinez-Arias A.
Curr Opin Neurobiol. (2021) 66: 240-249
Direct Readout of Neural Stem Cell Transgenesis with an Integration-Coupled Gene Expression Switch.
Kumamoto T, Maurinot F, Barry-Martinet R, Vaslin C, Vandormael-Pournin S, Le M, Lerat M, Niculescu D, Cohen-Tannoudji M, Rebsam A, Loulier K, Nedelec S, Tozer S, Livet J
Neuron. 2020 Jun 17;S0896-6273(20)30407-4.
BMP4 patterns Smad activity and generates stereotyped cell fate organization in spinal organoids.
Duval N, Vaslin C, Barata TC, Frarma Y, Contremoulins V, Baudin X, Nedelec S, Ribes VC.
Development. 2019 Jul 25;146(14). pii: dev175430.
Serotonin neurons in a dish.
Patricia Gaspar, Stéphane Nedelec
Nat Biotechnol. 2016 Jan;34(1):41-2.
Combinatorial analysis of developmental cues efficiently converts human pluripotent stem cells into multiple neuronal subtypes.
Yves Maury, Julien Côme, Rebecca A Piskorowski, Nouzha Salah-Mohellibi, Vivien Chevaleyre, Marc Peschanski, Cécile Martinat, Stéphane Nedelec
Nat Biotechnol. 2015 Jan;33(1):89-96.
Synergistic binding of transcription factors to cell-specific enhancers programs motor neuron identity.
Esteban O Mazzoni, Shaun Mahony, Michael Closser, Carolyn A Morrison, Stephane Nedelec, Damian J Williams, Disi An, David K Gifford, Hynek Wichterle
Nat Neurosci. 2013 Sep;16(9):1219-27.
Genetically-modified human pluripotent stem cells: new hopes for the understanding and the treatment of neurological diseases?
Stéphane Nedelec, Brigitte Onteniente, Marc Peschanski, Cécile Martinat
Curr Gene Ther. 2013 Apr;13(2):111-9.
Concentration-dependent requirement for local protein synthesis in motor neuron subtype-specific response to axon guidance cues.
Stéphane Nédelec, Mirza Peljto, Peng Shi, Mackenzie W Amoroso, Lance C Kam, Hynek Wichterle
J Neurosci. 2012 Jan 25;32(4):1496-506.
An alternative splicing switch regulates embryonic stem cell pluripotency and reprogramming.
Mathieu Gabut, Payman Samavarchi-Tehrani, Xinchen Wang, Valentina Slobodeniuc, Dave O’Hanlon, Hoon-Ki Sung, Manuel Alvarez, Shaheynoor Talukder, Qun Pan, Esteban O Mazzoni, Stephane Nedelec, Hynek Wichterle, Knut Woltjen, Timothy R Hughes, Peter W Zandstra, Andras Nagy, Jeffrey L Wrana, Benjamin J Blencowe
Cell. 2011 Sep 30;147(1):132-46.