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Generation of Functional Human 3D Cortico-Motor Assembloids.

Jimena Andersen1, Omer Revah1, Yuki Miura1

  • 1Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis Program, Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA 94305, USA.

Cell
|December 17, 2020
PubMed
Summary

Researchers created functional 3D human brain-spinal cord-muscle circuits (assembloids) for studying movement generation and neurological diseases.

Keywords:
assembloidscerebral cortexconnectivitycorticospinalhuman pluripotent stem cellsneuromuscularoptogeneticsorganoidsrabies tracingspinal cord

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Area of Science:

  • Neuroscience
  • Developmental Biology
  • Tissue Engineering

Background:

  • Descending pathways from the cerebral cortex control movement by activating hindbrain and spinal cord neurons.
  • Previous in vitro studies generated components but not a complete multi-synaptic circuit with human cells.

Purpose of the Study:

  • To assemble functional 3D human cortico-motor assembloids using organoids and muscle spheroids.
  • To investigate the self-assembly and functionality of human neural circuits controlling movement.

Main Methods:

  • Derivation of cerebral cortex and hindbrain/spinal cord organoids from human cells.
  • Assembly of organoids with human skeletal muscle spheroids into 3D cortico-motor assembloids.
  • Utilized rabies tracing, calcium imaging, and patch-clamp recordings to assess circuit connectivity and function.

Main Results:

  • Demonstrated corticofugal neurons projecting to and connecting with spinal cord organoids.
  • Confirmed spinal motor neurons connecting with muscle spheroids, enabling muscle contraction upon stimulation.
  • Assembloids remained morphologically and functionally intact for up to 10 weeks.

Conclusions:

  • 3D cortico-motor assembloids represent a novel in vitro model for studying human neural circuit assembly and function.
  • This system showcases the self-assembly capacity of 3D cultures for creating functional circuits.
  • The assembloids provide a platform for understanding motor control development and neurological diseases.