"Science" breakthrough: New research brings new understanding of such diseases that only affect the human brain

▎Edited by WuXi AppTec Content Team The complex brain is one of the proudest unique features of the self-proclaimed "Spirit of All Things"
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However, the complexity of the human brain also has a price.
Some diseases involve cell types or developmental processes that are unique to the human brain.
Not only have they become "exclusive" to humans, it is even difficult to figure out what the disease is
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For example, when fighting other diseases, scientists often use various animal models, but this method cannot accurately simulate the changes in the human brain
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Image source: 123RF Recently, a research team from the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences has brought about a breakthrough
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Using patient-derived cells, they grew "organoids" that mimic the brain, revealing how a rare neurodevelopmental disorder occurs and pointing to future directions for the treatment of related diseases
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The result was recently published in the top academic journal "Science", and the magazine also published an expert review in the same issue, which introduced it, pointing out that "this work changes our understanding of neurodevelopmental diseases and sheds light on human brain development.
key aspects"
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Professor Jürgen Knoblich, who is in charge of this research, is an academician of the Austrian Academy of Sciences.
In 2013, he and his collaborators made a sensational work around the world.
For the first time, they established "human brain organoids" from human induced pluripotent stem cells (iPSCs).
"Model, that is, in a culture medium that simulates the environment of brain development, these stem cells are differentiated to produce three-dimensional tissue that can mimic the human brain
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By further optimizing this revolutionary technology, researchers are beginning to challenge neuropsychiatric diseases that have long been difficult to study
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In this study, they focused on a disease called tuberous sclerosis complex (TSC, or tuberous sclerosis complex)
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▲ "Science" made a special report on the study.
TSC is a rare neurodevelopmental disorder.
Patients may develop tumors in the skin, brain, kidneys and lungs.
Due to the damage to the nervous system, most of them will also show severe epilepsy.
As well as aggressive behavior, autism, learning difficulties and other mental problems
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The disorder also involves marked changes in brain morphology, such as the appearance of multiple nodules on the surface of the brain and on the ependyma
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In past studies based on animal models, TSC has been considered to be mainly a genetic problem, that is, mutations in the TSC1 or TSC2 genes
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In this study, however, the scientists found that the problem stems primarily from developmental processes
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▲Schematic diagram of the research method (Image source: Reference [1]) The researchers obtained cells from several patients with tuberous sclerosis complex with TSC2 mutations, and cultured human brain organoids to analyze the development process of the patient’s brain Molecular and cellular mechanisms at specific moments
in
"With this approach, we found that organoids can grow tumor-like in patients' brains, with disorganized nodule-like structures
,
" describe the study authors
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▲ Human brain organoids derived from TSC patients were cultured for 230 days, and immunostaining with markers of human interneurons could identify aggregates of malformed interneurons (Image source: Reference [3]; Credit: Knoblich/IMBA) used single-cell sequencing, histological analysis and other methods to further unearth the cause.
The researchers found that the tumors and nodules in the TSC brain are related to a type of cell unique to the human brain, which overproliferates in the middle embryonic development.

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Such cells are located in the caudal ganglion process (CGE) and are known as caudal late interneuron progenitors (CLIP cells)
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This progenitor cell type has not been found in animals such as mice in the past, and is in fact a type of cell that accompanies the expansion of the human brain
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▲ In mid-gestation, CLIP cells residing in caudal ganglion processes give rise to interneurons that migrate to the cortex, but in the TSC context, heterozygous mutations in TSC2 lead to hyperproliferation of CLIP cells, resulting in cortical nodules and brain tumors (image source).
: Reference [3]; Credit: Knoblich/IMBA) "When we were looking for the root cause of TSC, we found that it was caused by a type of progenitor cell unique to the human brain
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This explains why it is not well established by other laboratory models establish the pathology of this disease,
"
commented Professor Knoblich
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In the researchers' view, human brain organoid models using patient cells not only pinpoint TSC pathogenesis to previously unknown cell types, but by identifying processes unique to human brain development, these findings may also be applicable to date.
Other diseases for which there is as yet no cure
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Reference: [1] Oliver L.
Eichmüller et al.
, (2022) Amplification of human interneuron progenitors promotes brain tumors and neurological defects.
Science Doi: 10.
1126/science.
abf5546[2] Rebecca Ihrie et al.
, (2022) Modeling tuberous sclerosis with organoids.
Science Doi: 10.
1126/science.
abn6158[3] Not all brains are equal: Why the human brain is more vulnerable to disease.
Retrieved Jan.
28, 2022 from https:// -releases/940862