Brain Organoids May Not Reproduce the Timing of Real Brain Development

The human brain develops through a carefully coordinated sequence of events. Certain cells must form before others so that neurons can migrate, connect and build precise neural circuits. However, new research suggests that miniature brain models, known as brain organoids, may not follow the same developmental timeline as a living brain.

A brain organoid is a laboratory-grown cluster of neurons and other brain-related cells that imitates some of the structural and functional features of a developing brain. Scientists use these “mini-brains” to study neurological diseases, including conditions that begin during fetal development.

Disruptions to the timing of brain development may contribute to conditions such as macrocephaly and microcephaly, in which the brain becomes abnormally large or small, respectively, according to study co-author Simon Hippenmeyer, a neuroscientist at the Austrian Institute of Science and Technology.

Because these conditions cannot be studied directly in living human fetuses, researchers often turn to brain organoids. But a study published Aug. 12 in the journal Nature suggests that these models may lack important components needed to accurately reproduce the timing and organization of real brain development.

Why timing matters in brain development

In earlier experiments involving mice, Hippenmeyer’s team tracked radial glial progenitors, or RGPs. These neuron-producing stem cells play a central role during early brain development.

To follow the cells’ development, the researchers gave pregnant mice drugs that activated fluorescent labels in individual stem cells. After the offspring were born, the team traced the labeled cells and determined how many neurons and other cells each stem cell produced at different stages of development.

The new study used the mouse data as a developmental reference point. Researchers compared it with mouse brain organoids grown from embryonic stem cells to determine whether the organoids produced cells in the same order as a developing brain.

The organoids produced the same major types of cells found in a developing brain. However, the sequence and timing of cell development were not preserved.

Brain organoids develop cells out of sync

During normal brain development, radial glial progenitors in the cerebral cortex divide and multiply before gradually producing neurons and glial cells. Glial cells support, nourish and insulate neurons.

In the brain organoids, however, some RGPs began producing neurons too early while other progenitor cells continued multiplying. This created a mismatch in the developmental timing of individual cells.

The researchers also found that RGPs in the organoids continued producing large numbers of descendants regardless of their developmental stage. In a developing brain, later-stage RGPs typically produce fewer cells than progenitors active earlier in development.

The team next examined the types of neurons produced by individual RGPs. The cerebral cortex contains six layers, and RGPs normally produce both deep-layer neurons during early development and upper-layer neurons during later development.

In the organoids, about one-third of the RGPs were restricted to producing only one of these neuron types. They could not generate the full range of neurons normally produced by their counterparts in a living brain.

What brain organoids are missing

A living brain contains blood vessels, extracellular structures and chemical signals linked to metabolism. These features are absent from most brain organoids, Hippenmeyer said. The researchers suspect that these external signals help coordinate when neurons develop and how they later form neural circuits.

“This suggests that there is something in the local environment of the cell [in the brain] that creates neurons,” said Denis Jabaudon, a neurobiologist at the University of Geneva who was not involved in the study. Scientists do not yet know exactly which signals are responsible.

For neurons to connect correctly, they must be in the right place at the right time, Jabaudon added. “If you shift the timing of development, you also shift the opportunities for connections and for certain circuits to form,” he told Live Science.

Could future organoids better mimic the brain?

The next step is to identify the external signals that developing neurons receive inside a living brain. Understanding these signals could help researchers determine why brain organoids differ from natural brain tissue.

Adding the missing signals to organoids could eventually make these models more accurate, allowing scientists to study brain development and neurological disorders in greater detail. Hippenmeyer’s team also plans to grow human brain organoids from human cells and investigate whether the same timing problems occur.

“We are very keen to understand how these radial glial stem cells operate within the human system,” Hippenmeyer told Live Science.

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