Human model of blood-brain barrier

The brain is a special organ for our body and thus all the more worthy of protection. And so the blood-brain barrier (BBB) prevents potentially harmful substances from the blood entering the brain. Disorders of this protective wall are involved in the development of major brain diseases such as strokes and Alzheimer’s.

Now researchers from LMU University Hospital, led by Professor Dominik Paquet and Professor Martin Dichgans from the Institute for Stroke and Dementia Research (ISD), have created a functioning human blood-brain barrier from human stem cells in the laboratory, for the purpose of investigating pathological processes. The findings of the scientists, together with lead authors Dr. Judit González Gallego and Dr. Katalin Todorov-Völgyi, have been published in the journal Nature Neuroscience.

In recent decades, hundreds of active pharmaceutical ingredients designed to tackle conditions like Alzheimer’s disease have appeared so promising in animal experiments that they have been subsequently tested on humans in elaborate studies. Only one of these was ultimately approved to treat patients.

This poor success rate illustrates how urgently drug development needs experimental models that are based on human cells and can better reproduce the effects and risks of potential new active ingredients. In addition, basic research relies on realistic models to decipher the genetic and molecular foundations of brain diseases such as Parkinson’s, Alzheimer’s, and strokes.

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One of the open questions, for example, is what role disorders of the blood-brain barrier play in neurological diseases. The BBB is a complex system of multiple cell types – especially endothelial cells of the innermost layer of blood vessel walls, but also smooth muscle cells and glial cells.

These cells form an almost impenetrable passive barrier, while also actively ensuring that substances that are important for the brain are let through and potentially dangerous substances from the blood are kept out. “In this way, the barrier creates a special environment in the brain, without which neurons couldn’t work efficiently,” explains LMU neuroscientist Paquet.

In 2018, his team began to recreate a model of the blood-brain barrier in the laboratory, based on induced pluripotent stem cells (iPSCs) from humans. Experts at the Institute for Stroke and Dementia Research (ISD) manufactured all the cell types required for a blood-brain barrier out of these iPSCs. With a few tricks from molecular and cell biology, the researchers got these cells to form functioning three-dimensional tissue in a gel-like matrix, which in microscopic images closely resembles blood vessels in the brain.

“In close collaboration with the laboratory of Martin Dichgans, we also managed to demonstrate that pathological processes can be researched in this model,” continues Paquet. “For example, we discovered that the blood-brain barrier no longer functions correctly when a so-called risk gene that occurs frequently in stroke patients is modified in the endothelial cells,” observes Dichgans.

The experimental system is now available to scientists worldwide who want to illuminate research questions relating to the blood-brain barrier. “It can be quickly established in any laboratory in just a few weeks,” says Paquet, who hopes the innovative model will accelerate the development of novel therapies for neurological diseases.

Martin Dichgans, Dominik Paquet et al. A fully iPS-cell-derived 3D model of the human blood–brain barrier for exploring neurovascular disease mechanisms and therapeutic interventions. Nature Neuroscience, 2025.