Miniature human brain models could boost drugs

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image: State-of-the-art neural organoids designed by Houston Methodist researchers are scalable, reproducible, and enable manipulation of neuron and astrocyte activity.
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Credit: Houston Methodist

HOUSTON – (February 9, 2022) – Diseases affecting the brain compromise not only the function of nerve cells, but also that of their support staff, the glial cells. In a new study, neuroscientists from Houston Methodist engineered neural organoids, also known as “miniature brains”, to contain both mature neurons and astrocytic glial cells in relative proportions similar to those of the human brain.

The research team, led by the main author Robert Krencik, Ph.D.assistant professor of Department of Neurosurgery to Neuroregeneration Center in the Methodist Research Institute in Houston, genetically engineered these organoids so that the activity of both cell types can be manipulated independently and on demand, facilitating the emulation of brain activity during healthy and diseased states. These improved properties open the door to multiple applications, including rapid drug screening for neurological diseases.

The study on this novel neural organoid technology, titled “Assessing Gq-GPCR-Induced Human Astrocytes Responsiveness Using Bioengineered Neural Organoids,” is published online in the Cell Biology Journal. Krencik is the corresponding author, and Caroline Cvetkovic, PhD, is the first author.

“The ultimate goal is to recapitulate nervous system functionality using organoids, and this study describes a next generation of this technology,” Krencik said. “Our new experimental procedure for producing the mature organoids is scalable, reproducible, and much faster than previous techniques, taking weeks rather than months.”

Organoids are 3D multicellular aggregates of cells created to simulate the structure and function of organs. These artificially generated mini-organs allow scientists to investigate questions that would otherwise require probing an organ in the body. Organoids offer an advantage over in vivo research with model organisms since the cell aggregates of organoids are derived from human stem cells, thus retaining key characteristics of human tissues.

Traditionally, brain organoids develop slowly from human pluripotent stem cells that differentiate into many cell types found in the human central nervous system. Some limitations of these organoids are that they contain a large number of cell types, including different subtypes of neurons, glial cells, and non-neural cells in different states of maturity. Therefore, studying the specific interactions between different cells poses a challenge.

“In the brain, synaptic connections between neurons develop and mature after astrocytes are born,” Krencik said. “Currently, using traditional methods, we have to wait several months for astrocytes to spontaneously generate in organoids.”

He added that even after astrocytes appear, organoids still take a long time to show brain-like activity characteristic of neural networks.

To address these shortcomings, Krencik and his team incorporated bioengineering techniques to rapidly generate neural organoids with defined populations of neurons and astrocytes produced independently from human pluripotent stem cells before combining them. The various forms of genetic manipulation they used allowed them to experimentally activate astrocytes with a chemical rather than waiting for the brain’s natural neurotransmitters to kick in, which is a longer and more complicated process. .

“By using two different technologies to target each cell type, we could selectively activate neurons or astrocytes,” Krencik said.

The researchers then combined the mature cultures of astrocytes and neurons to make spherical organoids, then recorded their electrical activity. When they activated neurons using blue light, they found they could evoke spikes from these cells to simulate the electrical activity of neural networks in the brain.

The effect of stimulating the engineered astrocyte receptor with a chemical depends on whether the activation is acute or chronic. When the researchers activated the astrocytes for a few hours, the cells increased expression of a variety of genes, especially those important for neurons to form synapses. When chronically activated, however, astrocytes at a reminiscent transition from the detrimental state of neuroinflammation. This hyperactivation appears to reduce neuron viability, but could be protected under more optimal conditions, indicating the external environment likely has an important role. Krencik says this could have implications for brain stimulation in the clinic, for example, where one must be careful not to stimulate too much.

“Our fully inducible organoid system is a useful tool not only for understanding the interactions between neurons and astrocytes in the healthy brain, but also how these connections are altered by disease,” Krencik said. “An exciting application for this technology is drug discovery. It can be scaled up very quickly to manufacture thousands of organoids at a time which can then be used as a high throughput testing platform for therapeutic drugs for different neurological diseases including Parkinson’s disease, Alzheimer’s disease and cancers of the nervous system.

This research is supported by grants from the National Institute on Aging of the National Institutes of Health (R21AG064567), the Mission Connect program of the Institute for Rehabilitation and Research Foundation (019-114), the Michael J. Fox Foundation for Parkinson’s Research (17871) and the Texas Institute for Cancer Prevention and Research (RP200655).

Other collaborators working on this study with Krencik and Cvetkovic, who is now with the University of Illinois at Urbana-Champaign, were Philip J. Horner, Matthew K. Hogan, Morgan Anderson, Nupur Basu, and Arya Shetty with the Department of Neurosurgery at the Center for Neuroregeneration at the Houston Methodist Research Institute; Rajan Patel, Debosmita Sardar and Benjamin Deneen with Baylor College of Medicine; Samira Aghlara-Fotovat and Omid Veiseh with Rice University; Srivatsan Ramesh with UT Health; and Michael E. Ward with the NIH National Institute of Neurological Disorders and Stroke.

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For more information: Evaluation of Gq-GPCR-induced responsiveness of human astrocytes using bioengineered neural organoids. Cell Biology Journal. (Online February 10, 2022) Caroline Cvetkovic Rajan Patel Arya Shetty, Matthew K. Hogan, Morgan Anderson, Nupur Basu, Samira Aghlara-Fotovat, Srivathsan Ramesh Debosmita Sardar, Omid Veiseh Michael E. Ward, Benjamin Deneen, Philip J. Horner and Robert Krencik. DO I: https://doi.org/10.1083/jcb.202107135

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