A pioneering achievement: the creation of the world's first small brain equipped with a functional blood-brain barrier A pioneering achievement: the creation of the world's first small brain equipped with a functional blood-brain barrier

A pioneering achievement: the creation of the world's first small brain equipped with a functional blood-brain barrier

A pioneering achievement: the creation of the world's first small brain equipped with a functional blood-brain barrier
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A team of scientists at Cincinnati Children's Hospital, the Mayo Clinic Foundation and the University of California, San Diego have made a discovery important for disease research and drug development.

During this pioneering achievement, the team developed the world's first mini-human brain that includes a fully functioning blood-brain barrier.

The human blood-brain barrier (hBBB), or blood-brain barrier, is defined as a barrier between the blood and the extracellular fluid (the sum of fluids found outside the cells in any multicellular organism) of the brain in the central nervous system.

This major advance, published on May 15, 2024, in the journal Cell Stem Cell, promises to accelerate understanding and improve treatment of a wide range of brain disorders, including stroke, cerebrovascular disorders, brain cancer, Alzheimer's disease, Huntington's disease, and Parkinson's disease. And other neurodegenerative conditions.

The breakthrough involves generating a blood-brain barrier that closely resembles the main features of the human blood-brain barrier.

Deciphering the blood-brain barrier

The blood-brain barrier (BBB) ​​is a selective, semi-permeable membrane that separates blood from the interstitial fluid of the brain. It enables the cerebral blood vessels to regulate the movement of molecules and ions between the bloodstream and the brain.

The brain's blood vessels are made up of an extra lining of tightly packed cells that limit the size of molecules that pass from the bloodstream into the central nervous system (CNS).

A properly functioning barrier is needed to maintain brain health by preventing harmful substances from entering the brain. At the same time, it allows essential nutrients to reach the brain.

However, the flaw here is that this barrier can prevent many potentially beneficial drugs from reaching the brain. Therefore, this latest breakthrough aims to solve this problem through stem cell bioengineering.

“Now, through stem cell bioengineering, we have developed an innovative platform based on human stem cells that allows us to study the complex mechanisms governing blood barrier function,” said Ziyuan Gu, lead author and faculty member in the Department of Developmental Biology at Cincinnati Children's Medical Hospital. "This provides unprecedented opportunities for drug discovery and therapeutic intervention."

This is the first time that a research center has succeeded in creating a brain organoid (a cellular organ designed in a laboratory) that features a special barrier lining found in the blood vessels of the human brain.

The researchers called this new model "BBB assembloids." The name reflects the advances that made this breakthrough possible, as the term assembloids refers to the feature of combining two or more organelles in laboratory models.

Through the new breakthrough, two different types of organoids were combined: brain organoids (those that replicate human brain tissue) and vascular organoids (those that mimic blood vessel structures).

The fusion process began with brain organoids with a diameter of 3 to 4 mm, and blood vessel organoids with a diameter of about one millimeter. Over the course of about a month, these separate structures coalesced into a single ball just over 4 mm in diameter (about the size of a sesame seed).

These integrated organoids recreate many of the complex neurovascular interactions observed in the human brain, but they are not complete models of the brain. For example, the tissues do not contain immune cells and have no connections with the rest of the body's nervous system.

In this breakthrough, the scientists used a line of patient-derived stem cells that create clusters that efficiently replicate the main features of a rare brain condition known as cerebral cavernous malformation, a genetic disorder characterized by a defect in the integrity of the blood-brain barrier, and leads to the appearance of clusters of abnormal blood vessels in the brain. The brain resembles a berry.

Gu noted that their model recapitulates the disease phenotype, which provides new insights into the molecular and cellular pathology underlying cerebrovascular disorders.

“Overall, blood-brain barrier assemblies represent a game-changing technology with broad implications for neuroscience, drug discovery and personalized medicine,” he explained.

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