USC scientists create the first whole human brain organoid model of the cerebellum with functional neurons

In a first for USC stem cell scientists, the lab of Giorgia Cuadrado, assistant professor of stem cell biology and regenerative medicine, has pioneered a new human brain organoid model that produces all major cell types of the cerebellum. Two cell types necessary for movement, cognition, and emotion: granule cells and Purkinje neurons. This is the first time scientists have succeeded in growing Purkinje cells that have the molecular and electrophysiological features of functional neurons in the entire human system. These advances in organoid-driven brain modeling were recently published in the journal The cell is the stem cell.

Reproducible co-growth and maturation of major cell types of the developing cerebellum in a human organoid model provides a new way to investigate the underlying biology of cerebellar development and disorders and advance therapeutic interventions.”

Georgia Cuadrado is an assistant professor in the Eli and Edith Pratt CIRM Center for Regenerative Medicine and Stem Cell Research at USC's Keck School of Medicine.

The cerebellum controls movement and plays an important role in cognitive functions including language, spatial processing, working memory, executive functions, and emotional processing.

Degeneration of Purkinje cells is associated with various neurodevelopmental and neurodegenerative disorders, including autism spectrum disorder and cerebellar ataxia, which affects muscle movement.

Other neurons within the organoids—excitatory neurons that share information and inhibitory neurons that inhibit information sharing—build circuits and display integrated network activity, demonstrating that they are also functional nerve cells. In addition, organoids produce human-specific progenitor cells that are associated with medulloblastoma, the most common metastatic brain tumor in children. This makes organoids a useful model for studying and discovering treatments for these pediatric cancers.

Given proper external cues, organoids can be assembled to form anatomical features such as layers that mimic normal embryonic brain development.

Organoid modeling creates a platform for discovering new treatments for various diseases.

„This study provides a physiologically relevant, all-human model system to elucidate cell type-specific mechanisms governing cerebellar development and disease,” said Alexander Atamian, a PhD candidate in the Cuadrado lab and first author. The cell is the stem cell study

Additional co-authors include Massella Birdele, Negar Hosseini, Duan Nguyen, Anoothi ​​Seth, Ashley Del Tosso, and Marcelo B. Koba from USC; Sandeep Paul, Neil Tedeschi and Ryan Taylor Spatial Genomics; Ranmal Samarasinghe from UCLA; and Carlos Lois from the California Institute of Technology.

The project was funded by Robert E. and May R. Funding was provided by the Wright Foundation, The Eli and Edith Pratt Foundation, and the Edward Mallinckdod, Jr. Foundation.