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Human Neural Organoids for Studying Brain Cancer and Neurodegenerative Diseases
Published on: June 28, 2019
Human neuromodulatory assembloids to study serotonin signaling and disease
Sabina Kanton1,2, Xiangling Meng1,2, Chunyang Dong1,2
1Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA.
Researchers created human brain organoids that model serotonin (5-hydroxytryptamine, 5-HT) signaling. These organoids revealed disease-related 5-HT defects, offering a new platform for studying neuropsychiatric disorders and drug development.
Area of Science:
- Neuroscience
- Developmental Biology
- Stem Cell Biology
Background:
- Neuromodulators are crucial for developing human brain functions and behavioral states.
- Dysfunction in neuromodulatory systems is linked to neuropsychiatric diseases, with many treatments targeting these pathways.
- Current human brain organoid models lack systematic incorporation of neuromodulation.
Purpose of the Study:
- To develop human brain assembloids that incorporate neuromodulation for studying brain development and disease.
- To investigate the role of serotonin (5-hydroxytryptamine, 5-HT) signaling in human brain organoids.
- To model 22q11.2 deletion syndrome (22q11.2DS) in vitro to understand its impact on 5-HT dynamics.
Main Methods:
- Generation of human midbrain-hindbrain organoids (hMHO) and human cortical organoids (hCO) from induced pluripotent stem cells (hiPSCs).
- Fusion of hMHO and hCO to create neuromodulatory assembloids (hNMA).
- Characterization of serotonergic neuron (5-HT neurons) development and function within hMHO and hNMA, including gene expression and electrophysiology.
- Assessment of 5-HT release and modulation of cortical network activity in hNMA.
- Modeling of 22q11.2DS using patient-derived hiPSCs and evaluation of 5-HT dynamics and therapeutic rescue with SSRIs.
Main Results:
- Development of functional 5-HT neurons within hMHO, exhibiting characteristic gene expression and electrophysiological properties.
- Integration and projection of 5-HT neurons from hMHO into hCO within hNMA, leading to 5-HT release and modulation of cortical activity.
- Aberrant 5-HT dynamics observed in hNMA derived from 22q11.2DS patient hiPSCs.
- Successful rescue of aberrant 5-HT dynamics in 22q11.2DS hNMA models upon treatment with a selective serotonin reuptake inhibitor (SSRI).
Conclusions:
- Human neuromodulatory assembloids (hNMA) provide a novel platform for studying human neuromodulation, particularly serotonin signaling.
- hNMA can recapitulate disease-specific phenotypes related to 5-HT dynamics, as demonstrated in a model of 22q11.2DS.
- This system holds potential for advancing the understanding of neuropsychiatric diseases and facilitating the development of targeted therapeutics.
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