Generation of human cerebral organoids with a structured outer subventricular zone
Ryan M. Walsh,
Raffaele Luongo,
Elisa Giacomelli,
Gabriele Ciceri,
Chelsea Rittenhouse,
Antonietta Verrillo,
Maura Galimberti,
Vittoria Dickinson Bocchi,
Youjun Wu,
Nan Xu,
Simone Mosole,
James Muller,
Elena Vezzoli,
Johannes Jungverdorben,
Ting Zhou,
Roger A. Barker,
Elena Cattaneo,
Lorenz Studer,
Arianna Baggiolini
Affiliations
Ryan M. Walsh
Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Raffaele Luongo
Institute of Oncology Research (IOR), Bellinzona Institutes of Science (BIOS+), 6500 Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6900 Lugano, Switzerland
Elisa Giacomelli
Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Gabriele Ciceri
Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Chelsea Rittenhouse
Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine Graduate School of Medical Sciences, Department of Neuroscience, New York, NY 1300, USA
Antonietta Verrillo
Institute of Oncology Research (IOR), Bellinzona Institutes of Science (BIOS+), 6500 Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6900 Lugano, Switzerland
Maura Galimberti
Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122 Milan, Italy; INGM, Istituto Nazionale Genetica Molecolare, 20122 Milan, Italy
Vittoria Dickinson Bocchi
Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Youjun Wu
The SKI Stem Cell Research Facility, The Center for Stem Cell Biology and Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
Nan Xu
Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, New York, NY 10065, USA
Simone Mosole
Institute of Oncology Research (IOR), Bellinzona Institutes of Science (BIOS+), 6500 Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6900 Lugano, Switzerland
James Muller
Developmental Biology and Immunology Programs, Sloan Kettering Institute, New York, NY 10065, USA
Elena Vezzoli
Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122 Milan, Italy; INGM, Istituto Nazionale Genetica Molecolare, 20122 Milan, Italy
Johannes Jungverdorben
Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
Ting Zhou
The SKI Stem Cell Research Facility, The Center for Stem Cell Biology and Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY 10065, USA
Roger A. Barker
Cambridge Stem Cell Institute and John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Forvie Site, University of Cambridge, Cambridge, UK
Elena Cattaneo
Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122 Milan, Italy; INGM, Istituto Nazionale Genetica Molecolare, 20122 Milan, Italy
Lorenz Studer
Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Weill Cornell Medicine Graduate School of Medical Sciences, Department of Neuroscience, New York, NY 1300, USA; Corresponding author
Arianna Baggiolini
Institute of Oncology Research (IOR), Bellinzona Institutes of Science (BIOS+), 6500 Bellinzona, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6900 Lugano, Switzerland; Corresponding author
Summary: Outer radial glia (oRG) emerge as cortical progenitor cells that support the development of an enlarged outer subventricular zone (oSVZ) and the expansion of the neocortex. The in vitro generation of oRG is essential to investigate the underlying mechanisms of human neocortical development and expansion. By activating the STAT3 signaling pathway using leukemia inhibitory factor (LIF), which is not expressed in guided cortical organoids, we define a cortical organoid differentiation method from human pluripotent stem cells (hPSCs) that recapitulates the expansion of a progenitor pool into the oSVZ. The oSVZ comprises progenitor cells expressing specific oRG markers such as GFAP, LIFR, and HOPX, closely matching human fetal oRG. Finally, incorporating neural crest-derived LIF-producing cortical pericytes into cortical organoids recapitulates the effects of LIF treatment. These data indicate that increasing the cellular complexity of the organoid microenvironment promotes the emergence of oRG and supports a platform to study oRG in hPSC-derived brain organoids routinely.
