How can the human brain grow so large? IMBA researchers find the key in neurodevelopment

The human brain contains many more neurons than those of other animals. But how are we able to produce so many neurons? Jürgen Knoblich and his team at IMBA have discovered that some human neuronal stem cells can replicate for far longer than expected and produce most neurons in the brain. Their findings, published in Nature Cell Biology on May 7, support a new model to explain the human brain’s unique development.

The human brain is so much more powerful than that of other animals, thanks to both brain size and complexity: our brains contain up to 86.000 million neurons, while the brain of a mouse contains only 75 million. This enormous number of neurons allows humans to have more specialized and efficient brain regions to perform advanced tasks. 

But how can the developing human brain generate so many neurons compared to other animals? So far, this question has remained unanswered, as models that could recapitulate the incredible development of the human brain have been lacking. Now, a multidisciplinary effort by Jürgen Knoblich and his team at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences, including Dominik Lindenhofer, Christopher Esk and Jamie Littleboy, as well as Simon Haendeler at the Center of Integrative Bioinformatics of the University of Vienna, has finally answered this question. Their results were published on May 7 in the journal Nature Cell Biology. 

Probing neurodevelopment in human brain organoids 

In order to study human brain development, the team used brain organoids, three-dimensional models derived from stem cells. The researchers combined this technology with lineage tracing: “We inserted a unique genetic barcode to each starting stem cell,” explains Christopher Esk. “When a cell replicates, all daughter cells inherit the same barcode, allowing us to track where each cell came from”. This novel tracing technique allowed the team to make an important discovery: while all stem cells contributed to the final organoid, there was a large difference between how many neurons each stem cell gave rise to.  

A small subpopulation of about 5% of stem cells were responsible for generating up to 80% of the final neurons,” explains Esk. The team’s discovery contradicted most existing models of neuronal development, and hinted at the fact that some stem cells may behave differently than others. 

Science Meets Math: Unraveling Neurodevelopment with Mathematical Modeling 

In order to make sense of the data they had observed, the scientists turned to math. Using computational biology, the team developed a mathematical model to predict the division behavior of the different cellular lineages. “The only explanation for our data is that some long-lasting neuronal stem cells keep dividing symmetrically way longer than we expected,” explains Simon Haendeler. Symmetric division allows stem cells to expand their numbers, while asymmetric division makes them differentiate into neurons. “Our model suggests that long-term symmetrically dividing stem cells give rise to most neuronal cell populations in the human brain.” adds Jamie Littleboy, PhD student at Jürgen Knoblich’s lab and co-author of the work. “This is very different to what we find in the mouse brain, where symmetric division is absent after the first four or five days of development.” 

How Neurodevelopment Adapts to Defects and Damage 

To further understand the process of neuron formation in brain organoids, the team decided to study what happens when some of the starting stem cells die. Interestingly, they showed that even if only a very small percentage of neuronal stem cells survived, the remaining cells were still able to generate all brain tissues. “With at least 10% of surviving cells, all brain structures and neuronal types are still formed correctly,” Jürgen Knoblich explains. The team’s results highlight the incredible resilience of neuronal stem cells, and how their plasticity can compensate for severe growth defects. 

The team now aims to study how this adaptation works: “We’re interested in identifying how cells sense that other cells are dying, and which compensatory mechanisms lead to tissue regeneration,” Knoblich adds. 

The techniques developed by the team establish a new platform to study lineage specification in organoids. These techniques can be applied to other types of organoids representing different organs.