Synchronous 3D patterning of diverse CNS progenitors generates motor neurons of broad axial identity

Research output: Preprint/Documentation/ReportPreprint

Contributors

  • Felix Buchner - , German Center for Neurodegenerative Diseases (DZNE) - Partner Site Dresden (Author)
  • Zeynep Dokuzluoglu - , German Center for Neurodegenerative Diseases (DZNE) - Partner Site Dresden (Author)
  • Joshua Thomas - , German Center for Neurodegenerative Diseases (DZNE) - Partner Site Dresden (Author)
  • Antonio Caldarelli - , German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Shrutika Kavali - , German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Fabian Rost - , DRESDEN-concept Genome Center (CMCB Core Facility), Max Planck Institute of Molecular Cell Biology and Genetics (Author)
  • Tobias Grass - , German Center for Neurodegenerative Diseases (DZNE) (Author)
  • Natalia Rodriguez Muela - , Selective neuronal vulnerability in neurodegenerative diseases (Junior Research Group), Max Planck Institute of Molecular Cell Biology and Genetics, German Center for Neurodegenerative Diseases (DZNE) - Partner Site Dresden (Author)

Abstract

In vitro human organoid models have become transformative tools for studying organogenesis, enabling the generation of spinal cord organoids (SCOs) that mimic aspects of spinal cord biology. However, current models do not produce spinal motor neurons (spMNs) with a wide range of axial identities along spinal cord segments within a single structure, limiting their utility in understanding human neural axial specification and the selective vulnerability of spMN subpopulations in motor neuron diseases. Here, we present a novel approach to enhance spMN axial heterogeneity in an advanced SCO model derived from neural stem cells (NSCs) and retinoic acid (RA)-primed neuromesodermal progenitors (NMPs). RA priming guided NMP differentiation into caudal neural progenitors, generating SCOs enriched in spMNs with posterior axial identities. To further diversify spMN populations, we optimized differentiation by synchronously patterning NSCs with RA-primed NMPs. Incorporating an endothelial-like network and skeletal muscle cells enhanced the organoids’ physiological complexity and neural maturation and organoid cell viability. This comprehensive approach, termed CASCO, provides a robust platform to study human spMN specification and model neurodegenerative diseases.

Details

Original languageEnglish
Publication statusPublished - 17 Dec 2024
No renderer: customAssociatesEventsRenderPortal,dk.atira.pure.api.shared.model.researchoutput.WorkingPaper

External IDs

ORCID /0000-0003-1065-1870/work/181390512

Keywords

Sustainable Development Goals