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June 28, 2019

Neural networks built with human stem cells

Using human embryonic stem cells, the Jun Takahashi lab constructs neural circuits derived from cerebral organoids that show spontaneous individual and synchronized neural activities.

The cerebrum is the part of the brain that defines our personalities, our morals, and our intellect. Humans are recognized as having an especially developed cerebrum, which functions through a complex neural network. In its latest study, the Jun Takahashi laboratory uses organoid technology to produce cerebrum neural circuits that show spontaneous neural activities consistent of a functional neural network, giving them promise for the study of related diseases and drugs.

The generation of neurons and other cells in the brain from stem cells has opened the door to new understandings and treatments for horrible brain diseases. Indeed, last year, Prof. Takahashi announced a clinical trial on a cell therapy for Parkinson's disease using iPS cell technology. Cerebral organoids are three-dimensional tissue derived from stem cells and mimic cerebral development. They have been used to study developmental disorders like microcephaly seen with the Zika virus infection, but current technology is inadequate to study psychiatric diseases such as epilepsy and autism, which are thought to result from abnormal neural activities.

"Neural networks operate through a combination of individual and synchronized activities. These complex activities could be used to model defects or diseases in the cerebrum," says neurologist Hideya Sakaguchi, who first-authored the study at CiRA but has since moved to the Salk Institute in the United States.

Several groups have established cerebrum organoids, but recapitulating the neural activities has remained a challenge. The study found that the combination of classical dissociation culture and cerebrum organoid technology solved this problem.

"Through dissociation culture, broad neural networks formed in a self-organized manner," says Sakaguchi. 'Self-organized manner' means no external signal is needed to form the complex network."

Sakaguchi went on to explain that neural networks are known to form in a self-organized manner when starting with mouse cells, but his study is the first to demonstrate this phenomenon with live imaging and calcium analysis using human cells.

The neural activity depended on the respective inhibitor and excitatory neurotransmitters GABA and glutamate, whose imbalance is associated with psychiatric diseases. Consistently, the study showed that the density of GABAergic neurons and glutamatergic neurons determines the burst type - individual or synchronized.

Adding to this feature, the scientists could modify the network behavior with drugs. CNQX is a drug that block certain types of glutamate receptors. As expected, neural networks exposed to CNQX showed disrupted synchronized activity, suggesting the potential of the organoids for studying complex neural diseases.

"We have been able to study drugs on individual cells, but we currently did not have good models for psychiatric and other diseases caused from functional dysregulations in the network. One of our goals is to make a model for drug screening," says Sakaguchi.

Paper Details
  • Journal: Stem Cell Reports
  • Title: Self-organized synchronous calcium transients in a cultured human neural network derived from cerebral organoids
  • Authors: Hideya Sakaguchi1, Yuki Ozaki1, Tomoka Ashida1, Takayoshi Matsubara2, Naotaka Oishi3, Shunsuke Kihara1, and Jun Takahashi1
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
    2. Life Science Center, MB, HQ, Yokogawa Electric Corporation, Ishikawa, Japan
    3. Informatics Japan, PerkinElmer Japan, Co., Ltd., Tokyo, Japan
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