26 May 2015

A model of the cerebral cortex in the form of tiny spheres

Researchers at Stanford University Medical School, working under the guidance of Dr. Sergiu Pasca, have proposed a method for creating spheres of neuronal cells similar in function to the cerebral cortex. This development will allow for the first time to use a functional model of brain tissue to study neuropsychiatric diseases such as autism and schizophrenia.

On a cross-section of spheroids, which are a model of the human cerebral cortex,
nerve progenitor cells (green) are visible against the background of non-dividing nerve cells (red).

The human brain is a highly organized three-dimensional mass of cells responsible for all the movements, thoughts and emotions of its host. Packed tightly inside the skull, it is a very difficult object to study.

The authors managed to make this task a little easier by creating spherical spheres floating freely in the environment from human brain cells, the structure of which is similar to the structure of the cortex – the outer layer of the brain responsible for how we perceive the world around us and interact with other people. The structure of such spheres includes functional neurons, functioning synapses and even astrocytes – auxiliary cells necessary to maintain the functionality of nervous tissue. At the same time, the gene expression profiles in the sphere cells correspond to the level of development of the embryonic human brain approximately in the middle of pregnancy.

Earlier attempts to create patient-specific neural tissue for research purposes either led to the appearance of two-dimensional colonies of immature neurons unable to form functional synapses, or required the use of an external matrix to grow cells in several time-consuming and technically complex stages.

Frustrated by the lack of a good model system for studying the development and functioning of the human brain, the researchers wanted to solve this problem on their own. To do this, they first created several batches of induced pluripotent stem cells (iPSCs) from the skin cells of five people. When cultivated under certain conditions, iPSCs have the ability to transform into almost all types of cells in the body.

The authors grew flat multicellular colonies from these cells, which were subsequently carefully removed from the cultivation surface and transferred to special laboratory cups, the surface of which prevents cell adhesion. Within a few hours, the colonies began to collapse on their own and form spheres. Under the influence of a combination of growth factors and small molecules, after about 7 weeks, 80% of the cells included in the spheres expressed a protein marker of nervous tissue. Moreover, approximately 7% of the cells expressed another protein synthesized exclusively by astrocytes – auxiliary cells with a stellate structure that form a shell around interneuronal contacts or synapses.

The authors note that the transmission of nerve impulses is impossible in the absence of astrocytes. However, no one has been able to receive neurons and astrocytes at the same time before. Until now, researchers have tried to grow neurons on the surface of a layer of astrocytes isolated from human or mouse embryonic tissue.

The diameter of the spheroids grown by scientists can reach about 5 mm. They can be maintained in the laboratory for at least nine months. At the same time, they demonstrate complex neural network activity and can be studied using techniques developed on animal models.

Functional testing of spheroid slices demonstrated that up to 80% of the neurons included in their composition had the ability to emit nerve impulses in response to stimulation. Moreover, 86% of neurons demonstrated spontaneous activity and were involved in the overall activity of the neural system. In other words, slices of spheroids behaved similarly to slices of brain tissue.

The researchers hope that observing the development and maturation of the spheroid model of the cerebral cortex, as well as the interaction of their constituent cells, will shed light on the development of the human brain and the molecular causes of neuropsychiatric diseases such as autism and schizophrenia.

Article by Anca M Paşca et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture is published in the journal Nature Methods.

Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Stanford University Medical Center:
Tiny spheres of human cells mimic the brain, researchers say.


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