A team of molecular biologists from the Austrian Academy of Sciences has now demonstrated that some human neural stem cells can multiply for a much longer period than expected and produce that large number of neurons. This finding, published in the journal Nature Cell Biology, offers a new explanation for the unique development of our human brain.

The human brain is much more powerful than that of other animals, thanks to both its size and complexity. In the brain of a mouse, for example, there are 75 million neurons, compared to 86 billion in the human brain. This incredibly large number of neurons is responsible for the human brain’s potent and highly specialized regions capable of performing complex tasks.

But how can the developing human brain generate so many neurons compared to other animals? Until now, this question remained unanswered due to a lack of models that could replicate the incredible development of the human brain. Now, Jürgen Knoblich and his team at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (ÖAW), which also includes Dominik Lindenhofer, Christopher Esk, and Jamie Littleboy, along with Simon Haendeler from Arndt von Haeseler’s lab at the Center for Integrative Bioinformatics at the University of Vienna, have finally found an answer.

The team used cerebral organoids, three-dimensional models derived from stem cells, to observe and analyze the development of the human brain and its processes. The researchers combined this technology with lineage tracing: We added a specific genetic barcode to each initial stem cell, explains Christopher Esk. When a cell replicates, all its daughter cells inherit the same barcode, allowing us to track where each cell came from. This new tracing technique led to a significant discovery: while all stem cells contributed to the final organoid, each produced a different number of neurons.

Approximately 5% of the stem cells were responsible for the formation of up to 80% of the final neurons, Esk explains. This finding contradicts existing models of neuronal development and suggests that some stem cells do not behave the same as others.

Immunofluorescence images of RFP and GFP signal together with choroid plexus tissue marker (TTR) staining in the chimeric RFP-WT:GFP-WT (a) and RFP-WT:GFP-KO-PAX6 (b) organoids
Immunofluorescence images of RFP and GFP signal together with choroid plexus tissue marker (TTR) staining in the chimeric RFP-WT:GFP-WT (a) and RFP-WT:GFP-KO-PAX6 (b) organoids. Credit: D. Lindenhofer et al. / Nature Cell Biology

The scientists used mathematics and computational biology to better understand the data. The team designed a mathematical model to calculate the division behavior of the various cell lines. The only explanation for our data is that in the human brain, some long-lived neural stem cells divide symmetrically for much longer than previously assumed, explains Simon Haendeler. Symmetric division allows stem cells to increase in number, while asymmetric division causes them to differentiate into neurons.

Our model shows that most of the neuronal populations in the human brain arise from long-term symmetrically dividing stem cells, adds Jamie Littleboy, a doctoral student in Jürgen Knoblich’s lab and co-author of the study. This is very different from what happens in the mouse brain. In mice, symmetric division does not occur after the first four or five days of development.

To better understand the process of neuron formation in cerebral organoids, the team decided to investigate what happens when some of the initial stem cells die. Interestingly, the researchers observed that even when very few neural stem cells remained, these few cells were still capable of forming the entire brain tissue.

With at least 10% surviving cells, all brain structures and neuron types still form correctly, says Jürgen Knoblich. The team’s results illustrate the incredible resilience of neural stem cells, which can even compensate for severe growth defects thanks to their plasticity.

The team now wants to investigate how this adaptation works: We want to find out how cells recognize that other cells are dying and what compensatory mechanisms lead to tissue regeneration, Knoblich continues. The techniques developed by the team create a new basis for researching cell type specification in organoids. They can also be used in organoids of other human organs to reveal the processes involved in the development of different organs.

Sources

Academia Austríaca de las Ciencias (ÖAW) | Lindenhofer, D., Haendeler, S., Esk, C. et al. Cerebral organoids display dynamic clonal growth and tunable tissue replenishment. Nat Cell Biol (2024). doi.org/10.1038/s41556–024–01412-z

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