New instrument maps cell sorts in lab-grown blobs of mind tissue | Spectrum
Map Quest: Two types of neurons (cortical, top; thalamus, bottom) from different organoid batches are mapped onto a reference view of the developing mouse brain. Dark colors indicate a high degree of similarity between the organoid-derived neurons and the reference map.
A new tool is helping researchers study the types of cells that make up the brain’s organoids – clusters of cells that can mimic the basic structure, function, and development of different parts of the brain.
The software, detailed in Cell Stem Cell, maps information about when and where genes are expressed in brain organoids to a reference atlas of the developing mouse brain. Scientists can use the resulting overlay to engineer organoids that better recapitulate the developing brain, the team says, or to uncover the effects of gene mutations and other experimental disorders.
Brain organoids obtained from the cells of people with conditions such as autism have been shown to be useful in detecting neural abnormalities. However, the results are clouded by methodological differences in the development of these lab-grown blobs. Advanced techniques for profiling gene expression in individual cells have made it easier to identify the cell types in a particular organoid. However, it remained difficult to map these cell types to different brain regions.
“You have to do a bit of detective work to find out what type of cells and which brain region you have grown,” says study director Barbara Treutlein, professor of quantitative developmental biology at ETH Zurich.
Treutlein and her colleagues developed a computer tool called VoxHunt, which maps the gene expression data of individual cells from brain organoids, which were obtained using various protocols, onto the Allen Mouse Brain Atlas. The atlas, the most detailed of its kind, provides a high-resolution, three-dimensional map of the developing mouse brain, including the expression patterns of more than 2,000 genes.
The researchers tested VoxHunt on data from experiments that recorded gene expression in individual cells of different types of brain organoids. Cells identified as cortical neurons based on their gene expression patterns map a developing region that makes up the outer layer of the brain, the team found. Cells identified as thalamic neurons are associated with the diencephalon, a region that develops into the thalamus and other brain structures.
With VoxHunt, the team identified a previously unknown cell cluster in 1-month-old organoids of the brain. These cells map structures like the roof plate, which produces molecules that are important for early brain development.
VoxHunt also maps data from experiments that map unwound regions of chromatin – the complex of DNA and proteins that helps regulate gene expression – in organoids of the brain. These developed regions are accessible to proteins that turn genes on and off. Knowing where cells with accessible chromatin regions are mapped on the reference atlas can be particularly useful for autism researchers, says Treutlein, since genes that influence chromatin structure are often mutated in people with neurodevelopmental disorders.