Assembling Human Cellular Models to Study Neurodegeneration

We propose to leverage technology we developed in the lab to build self-organizing 3D human cellular systems that capture neural-glial interactions and inter-regional neural cross-talk. We will use this powerful preparation, also known as brain assembloids, to uncover the programs underlying prolonged maturation of neurons and astrocytes in humans and model specific genetic forms of neurodegenerative disorders. This work could lead to novel strategies and tools for modeling brain maturation and neurodegeneration with patient-derived cells and could ultimately bring therapeutic insights.

This project has made a number of key advances, including:

• Developing striatal organoids and modeled cortico-striatal connectivity in assembloids
• Developing spinal cord organoids and muscle spheroids, and generating functional cortico-spinal-muscle circuits in assembloids
• Creating several human cellular models of disease with patient-derived cells (Timothy syndrome, Phelan McDermid syndrome, 22q11 deletion syndrome), and dissected the molecular mechanisms of these conditions
• Generating single cell cell atlases of the developing human cerebral cortex and human spinal cord

The lab has developed detailed protocols for generating regionalized neural organoids and assembloids, organized hands-on workshops on organoids and assembloids, and performed single cell profiling of the developing central nervous system and generated gene expression profiles of cortical organoids over time.