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

Publikation: Vorabdruck/Dokumentation/BerichtVorabdruck (Preprint)

Beitragende

  • Felix Buchner - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) - Standort Dresden (Autor:in)
  • Zeynep Dokuzluoglu - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) - Standort Dresden (Autor:in)
  • Joshua Thomas - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) - Standort Dresden (Autor:in)
  • Antonio Caldarelli - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) (Autor:in)
  • Shrutika Kavali - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) (Autor:in)
  • Fabian Rost - , DRESDEN-concept Genome Center (CMCB Core Facility), Max Planck Institute of Molecular Cell Biology and Genetics (Autor:in)
  • Tobias Grass - , Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) (Autor:in)
  • Natalia Rodriguez Muela - , Selektive Neuronale Verwundbarkeit bei Neurodegenerativen Erkrankungen (NFoG), Max Planck Institute of Molecular Cell Biology and Genetics, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) - Standort Dresden (Autor:in)

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

OriginalspracheEnglisch
PublikationsstatusVeröffentlicht - 17 Dez. 2024
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Externe IDs

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

Schlagworte

Ziele für nachhaltige Entwicklung