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Mini-organ research identifies ‘traffic light’ in development of gut cells

Research into the normal development of cells in the body is a key part of understanding how childhood cancer develops. Scientists at the Hubrecht Institute and the Princess Máxima Center have found a gene that controls how specific cells in the gut specialize into hormone-producing cells. These cells are faulty in a number of rare forms of childhood cancer. The discovery could also help better understand the problems in hormone production that can occur in children who have survived their cancer.

The gut contains various cell types, each with specific functions. These cell types all arise from the stem cells of the gut. In a new study, published in the journal Science today, researchers from the Organoid group at the Hubrecht Institute worked with colleagues at the Princess Máxima Center. They investigated how stem cells develop into a specific kind of gut cell known as enteroendocrine cells (EECs). They carried out their study using gut organoids: lab-grown mini-organs that mimic the structure and function of the actual gut.

Stem cell traffic lights

The differentiation of stem cells into specific cell types occurs through gene regulation: the ‘on’ and ‘off’ switching of genes in the DNA of the cells. Dr. Lin Lin, postdoc in the Clevers e.t. groups at the Hubrecht and the Máxima Center, explains: ‘You can compare it to a bustling intersection where different roads lead to various cell destinies. The cars on the roads represent different cell types. The transcription factors act as traffic lights at the intersections, determining whether cells can follow a particular direction to become specialized cells. In our study, we used CRISPR technology, a gene-editing tool, to specifically target individual on and off switches for those ‘traffic lights’. We did this to uncover the intricate signaling system that directs cells down their predetermined routes.’

Master repressor gene

The researchers looked at 1800 genes to find protein switches involved in stem cell differentiation into EECs, the hormone-producing cells in the gut. The team found a gene called ZNF800, which acted as a critical off-switch in determining the balance between EECs and other cell types in the gut. Lin: ‘We showed that ZNF800 acts as a so-called master repressor, meaning that it influences other DNA-switches and, in the end, blocks stem cells from developing into EEC cells.’

Jeff DeMartino is a PhD-student in the Drost group at the Máxima Center. He helped study which genes were active in the mini-gut organoids, using a method called gene expression analysis. He says: ‘We looked at how these on and off switches regulate changes in the expression of genes at the single cell level. It was surprising to find that ZNF800 had such a striking influence on the differentiation potential of gut stem cells.’

Clinical implications

The discoveries made by Lin and her colleagues could have implications for understanding diseases of the digestive system and hormone disorders. The development of EEC hormone-producing cells also plays a role in rare forms of childhood cancer called neuroendocrine tumors. Hormone disorders can also be a late effect of treatment for childhood cancer. Lin: ‘Our findings provide crucial insights into the molecular mechanisms that govern cell fate decisions in the human gut. This knowledge is essential for understanding these conditions and ultimately developing treatments.’