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Researchers at the Institute of Science and Technology Austria (ISTA) have developed a new mouse brain organoid model that allows them to compare brain development in the laboratory with development inside a living animal.

Their findings, published in Nature, could help researchers understand which aspects of brain development can be accurately studied using organoids.

Organoids are three-dimensional structures grown from stem cells. Over the past 15 years, scientists have developed organoids that mimic parts of organs such as the heart, gut and brain.

The team led by Stefan Hippenmeyer focused on the cerebral cortex, a region of the brain that contains large numbers of neurons and glial cells and plays a major role in cognition and brain function.

The researchers first developed a stable mouse stem cell line and used it to create cortical organoids in the laboratory. This provided a consistent system for studying how stem cells develop into different types of brain cells.

To find out how closely the organoids matched a real developing brain, the researchers compared them with mouse brains at specific stages of development.

Using single-cell sequencing, they examined the different cell types present in each system and studied when those cells appeared and disappeared.

The results showed that the organoids contained many of the same cell populations as the developing mouse brain. They also followed similar molecular programmes.

However, an important difference emerged when the scientists looked more closely at the timing of development.

In a living mouse, brain development follows a carefully organised sequence. Stem cells initially multiply, then switch to producing neurons and, once neuron production is complete, begin generating glial cells.

In the organoids, the same broad processes occur, but the timing is less coordinated. Neuronal development becomes uncoupled, meaning different developmental stages can overlap rather than following the precise sequence seen in a real brain.

The researchers describe this as the organoid keeping the hour but losing the minutes.

Scientists believe the difference may be linked to the environment surrounding stem cells.

Inside a living brain, stem cells are influenced by their surrounding environment, known as the stem-cell niche. This includes neighbouring cells, blood vessels, signalling molecules, growth factors and physical forces.

An organoid grown in a laboratory dish has access to far fewer of these external signals. Although it can organise itself into a structure resembling part of a brain, self-organisation alone may not be enough to reproduce the precise timing of development.

Brain organoids can reproduce many important features of development, making them valuable tools for studying diseases and developmental disorders such as microcephaly and macrocephaly.

At the same time, researchers need to understand where organoids differ from living brains before concluding.

The ISTA team now hopes to recreate elements of the stem-cell niche within organoids. By gradually adding signals found in the developing mouse brain, researchers may be able to improve the timing of organoid development and make these miniature brain models even more accurate.