'Mini-brains' created in the lab to help fight neurological diseases

What if scientists could grow tiny versions of the human brain, not just to observe them, but to uncover how disorders like autism or schizophrenia begin? With the help of cutting-edge technology, researchers are now recreating the earliest stages of brain development outside the womb using brain organoids.

Researchers at Johns Hopkins University (JHU) have developed these “mini brains,” a breakthrough in brain modeling that could reveal the origins of neurological diseases.

By mimicking the brain’s regions and blood vessels, scientists hope to improve their understanding of how these neurological conditions develop.

Brain organoids mimic early brain development

To understand how neurological diseases and conditions develop, scientists have created simplified versions of the brain called brain organoids.

These are three-dimensional tissue cultures that grow from stem cells and replicate the structure and function of the brain. 

More recently, they have developed brain assembloids, which are fusions of multiple brain organoids. They combine organoids representing different parts of the brain, such as the cortex, midbrain, and hindbrain.

Earlier models had several drawbacks. These limitations made it difficult to capture fully how the brain develops in the womb. 

To address these gaps in previous studies, the researchers from Johns Hopkins University developed Multi-Region Brain Organoids (MRBOs).

MRBOs are new-generation “mini brains” that accurately reflect the development and functioning of the fetal brain. 

They are created by combining brain organoids of the cerebrum, midbrain, and hindbrain, with blood vessel structures in the form of endothelial organoids.

It was found that in MRBOs, each area-specific organoid maintains a unique identity, just like in the developing human brain. 

What did earlier brain models miss?

Before MRBOs, researchers relied on brain assembloids that lacked one important feature: blood vessels across multiple brain regions.

Most studies did add blood vessel cells, called endothelial cells, but only to the cortex region of the brain model. These cells allowed for the formation of blood vessel-like structures, but in the cortex region alone. 

The researchers faced yet another challenge. For the studies, isolated blood vessel cells from the umbilical veins, called human umbilical vein endothelial cells (HUVECs), were used. 

However, HUVECs do not accurately represent the endothelial cells found in the brain, which are composed of a variety of specialized cell types.

This limitation prompted the team to develop a more precise and brain-relevant model of blood vessels.

Endothelial organoids for best mimicry

This was the point where endothelial organoids came into action. An endothelial organoid is a lab-grown, three-dimensional model that mimics real blood vessels. 

These structures contain multiple cell types, including vascular progenitors, mature endothelial pericytes, proliferating angiogenic cells, and stromal cells. This closely mimics the natural blood vessel environment of the brain.

Interestingly, recent studies have shown that endothelial cells marked by the CD31 protein can naturally arise in cerebral organoids. This is possible when bioreactors and microfluidic systems are used. 

The biomechanical tools maintain low shear stress, allowing gentle and low-pressure movement of the fluid that mimics natural blood flow. This encourages brain organoids to grow endothelial cells on their own.

These systems show the role of biomechanics in vascular differentiation. But they will only work when the organoid involves a single region of the brain.

Unlike MRBOs, these models do not incorporate the multicellular endothelial structure of blood vessels, which is a key feature of the normal brain.

Brain and blood vessels grow together

In human fetal development, the endothelial and neural systems develop side by side. The two systems communicate with each other constantly, and endothelial-derived signals guide the growth, identity, and organization of different brain areas.

These interactions are critical and should be considered while creating brain models to study neurological diseases. Ignoring them would not provide a complete picture of the development of neurological diseases.

MRBOs and complex brain disorders

The unique feature of MRBOs is that they include tissue types from the three main areas of the brain and are supplied with blood vessels.

This allows scientists to explore the highly complex functions of the brain and assess the effects of environmental factors, genetics, and therapy on neurodevelopment.

Most importantly, “mini brains” could help explain the mechanisms involved in the development of some neurological disorders, such as schizophrenia, autism spectrum disorder and bipolar disorder.

MRBOs may allow researchers to observe how abnormal development in specific brain regions leads to disorders like schizophrenia or autism.

Understanding these mechanisms will pave the way for earlier diagnosis, better treatment, and the development of effective preventive strategies.  

The full study was published in Advanced Science.

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