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Researchers in the Simmons lab chart the embryonic origins and appearance of diverse intestinal cellular compartments, with important implications for intestinal diseases.

In a new study, published in Cell, researchers from the Simmons and Koohy groups have mapped the gene expression of individual cells from the whole of the developing human gut, revealing new insights into the diverse cellular compartments needed for normal human development. The team hope that their work will provide a tool to understand how the intestine forms: they are providing free access to the resource online through an interactive app for other researchers to use.

The intestine is one of the largest barrier organs in the body and contains a huge variety of different cell types to undertake its important functions, including absorption and immune response. There is a tightly regulated process that must be completed before birth for the intestine to form. Dysregulation of this process can lead to disease, either in the form of rare congenital malformations or errors in the establishment of life long regenerative circuits that are needed for adult health.

Despite the importance of these processes, until now relatively little was known about the mechanisms that underlie human intestinal development. Much important information has been discovered using animal models, but due to the rarity of embryonic tissue from pre-natal disease it has been challenging to apply.

Mapping the human gut

In this study the researchers took fetal samples from the Human Developmental Biology Resources (HDBR, London) across multiple timepoints and locations in human development. This charted the changes happening from 8 to 22 weeks after conception– a period when the intestine goes from a flat tube to a folded surface with finger-like projections (called villi), as well as depressions (called crypts). 

Study lead Professor Alison Simmons, from the MRC HIU, said “Intestinal cells exhibit huge diversity, so to fully understand how these develop we first mapped all the cell types that contribute to its structure using single cell sequencing.

This was then linked with a new complimentary technique, Spatial Transcriptomics, which was able to place them within anatomical context. The advent of spatial sequencing technology has allowed us to harness the technique to see the precise molecular profiles of cells in tissue and how they changed during development”

Employing cutting-edge techniques 

The researchers used high-resolution single-cell technologies to map the gene expression of individual cells from the entire thickness of the developing gut. This included over 76,000 cells each expressing thousands of genes, and mapping their differences identified 101 different cell types. 

Data integration with Spatial Transcriptomics localised the formation of key intestinal cell types, and uncovered unappreciated diversity within cells that reflected their functions.

New insights into congenital diseases 

Study author David Fawkner-Corbett, from the MRC HIU, said “Our work reveals new insights on critical events during intestinal development, which are key for normal health at birth. It helps to define the origins of the diverse cells that will make up the adult intestine, and reveals new information on how, when and where they appear. This allows us to bring a new appreciation to their relationships and connectivity”

In another key finding, the resource was applied to a curated list of rare congenital intestinal diseases where pathology would usually occur before birth such as Hirschsprung’s disease and omphalocele. Although it would not normally be possible to study these in utero, mapping the genes linked to them with the atlas identified types of cells and time points where pathology would occur.

It is hoped that this work will provide a basis for other researchers to understand how the intestine forms, with all analysis available as an interactive online app – the Spatio-Temporal Analysis Resource of Fetal Intestinal Development (STAR-FINDer). The findings could translate to revealing the origins of congenital anomalies, understanding new information on how the intestine regenerates in health, and form a basis to appreciate what leads to dysregulation and inflammation.

This study was funded by the Medical Research Council, Wellcome Trust, the Oxford NIHR Biomedical Research Centre, the NIHR Clinical Research Network (CRN) Thames Valley, and the Lee Placito Medical Fund.

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