Better standards for creating brain organoids proposed

Conditions that are favourable to growing good quality brain organoids have been demonstrated by University of California scientists.

While organoids have created exciting new possibilities for scientists to study diseases in the lab, the lack of consistency in how they are grown can lead to different results.

'If my lab and another lab down the hall were to conduct drug screens using mini-brain organoid models of the same disorder, we could still get different results,' said Dr Momoko Watanabe, first author on the paper published in Stem Cell Report and assistant professor at University of California, Irving. 'We won't know whose findings are correct because the differences we're seeing could be reflections of how our models differ rather than reflections of the disease.'

This is of particular relevance for studies of the brain, which can have a very similar structure in people with different disorders, but functions differently.

'Every neuroscientist wants to make a brain organoid model of their favourite disease, and yet everyone's organoids do not always look alike.' said Bennett Novitch, professor of neurobiology at University of California, Los Angeles, and senior author on the paper. 'We'll never be able to identify the subtle differences in brain structure and function, things that are relevant for patients with neurological disorders, if our organoids have the wrong balance of cell types or grossly irregular structure,' he continued.

Organoids are grown from human induced pluripotent stem cells (iPSCs). They can be created from human skin or blood cells, and then made to differentiate into any of a number of different human cell types to form organoids. The quality of these organoids is impacted by how the iPSCs are maintained before they differentiate. In particular, stem cells should be at an intermediate or 'formative' stage of maturity. Stem cells that are too young need to more encouragement to differentiate, while older stem cells have already differentiated too much.

'In human embryonic development, the nervous system is one of the first structures to form, so it makes sense that stem cells that are early in development are best at producing brain organoids,' Dr Watanabe said.

The team showed that one way to keep iPSCs at an earlier level of development is to grow them alongside mouse cells.

They also found that similar organoids could be produced by growing the iPSCs without mouse cells but with a mix of four molecules from the transforming growth factor beta family. These could readily be transformed into cells from different regions of the brain.

According to the paper, the reported concentrations of the molecules should be viewed as starting guidelines and may need to be adjusted for different cell lines and that even under these conditions, labs could have different results.