Trans-omic profiling uncovers molecular controls of early human cerebral organoid formation

Carissa Chen; Scott Lee; Katherine G Zyner; Milan Fernando; Victoria Nemeruck; Emilie Wong; Lee L Marshall; Jesse R Wark; Nader Aryamanesh; Patrick P L Tam; Mark E Graham; Anai Gonzalez-Cordero; Pengyi Yang

doi:10.1016/j.celrep.2024.114219

Trans-omic profiling uncovers molecular controls of early human cerebral organoid formation

Cell Rep. 2024 May 28;43(5):114219. doi: 10.1016/j.celrep.2024.114219. Epub 2024 May 14.

Authors

Affiliations

¹ Computational Systems Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; Embryology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
² Stem Cell and Organoid Facility, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
³ Computational Systems Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
⁴ Stem Cell Medicine Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
⁵ Stem Cell Medicine Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
⁶ Bioinformatics Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
⁷ Synapse Proteomics, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia.
⁸ Bioinformatics Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
⁹ Embryology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia.
¹⁰ Synapse Proteomics, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: mgraham@cmri.org.au.
¹¹ Stem Cell and Organoid Facility, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; Stem Cell Medicine Group, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: agonzalez-cordero@cmri.org.au.
¹² Computational Systems Biology Unit, Children's Medical Research Institute, University of Sydney, Westmead, NSW 2145, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia; Charles Perkins Centre, School of Mathematics and Statistics, University of Sydney, Sydney, NSW 2006, Australia. Electronic address: pengyi.yang@sydney.edu.au.

PMID: 38748874
DOI: 10.1016/j.celrep.2024.114219

Abstract

Defining the molecular networks orchestrating human brain formation is crucial for understanding neurodevelopment and neurological disorders. Challenges in acquiring early brain tissue have incentivized the use of three-dimensional human pluripotent stem cell (hPSC)-derived neural organoids to recapitulate neurodevelopment. To elucidate the molecular programs that drive this highly dynamic process, here, we generate a comprehensive trans-omic map of the phosphoproteome, proteome, and transcriptome of the exit of pluripotency and neural differentiation toward human cerebral organoids (hCOs). These data reveal key phospho-signaling events and their convergence on transcriptional factors to regulate hCO formation. Comparative analysis with developing human and mouse embryos demonstrates the fidelity of our hCOs in modeling embryonic brain development. Finally, we demonstrate that biochemical modulation of AKT signaling can control hCO differentiation. Together, our data provide a comprehensive resource to study molecular controls in human embryonic brain development and provide a guide for the future development of hCO differentiation protocols.

Keywords: CP: Neuroscience; CP: Stem cell research; human cerebral organoid; neurodevelopment; organoid model; phospho-signaling; phosphoproteome; proteome; trans-omics; transcriptome.

MeSH terms

Animals
Brain* / embryology
Brain* / metabolism
Cell Differentiation*
Humans
Mice
Neurogenesis
Organoids* / metabolism
Pluripotent Stem Cells / cytology
Pluripotent Stem Cells / metabolism
Proteome / metabolism
Proteomics / methods
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Transcriptome / genetics

Substances

Proteome
Proto-Oncogene Proteins c-akt