Five years ago, researchers discovered that cells behave like fetal cells when repairing the epithelium of the intestine. Now the researchers have determined how the cells revert to this primitive fetal-like stage. A researchers says that the discovery may lead to the development of new drugs for improving wound healing.
Intestinal cells repairing the epithelium lining the intestine undergo a fascinating process of regressing to the fetal stage and acquiring the characteristics of the cells in the intestine during fetal development.
In this more primitive cell stage, the cells can divide more rapidly and thus repair the intestinal epithelium by replacing the lost tissue. Then the cells revert back to the adult stage, because this more effectively protects the intestinal epithelium from the environment.
The researchers discovered this ingenious mechanism for repairing the intestine 5 years ago, and now they have identified the genes, proteins and signalling pathways that set the biological clock and orchestrate the repair.
The discovery may eventually lead to the development of drugs that can improve wound healing.
“Now we understand better how these cell stages differ and how to induce the cells to transition from one stage to the other and back again. We hope that manipulating the identified components can stimulate tissue and improve wound healing,” explains a researcher behind the discovery, Kim Bak Jensen, Professor, Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, University of Copenhagen.
The results have been published in two studies in Science Advances.
Individual roles of two types of cells
Kim Bak Jensen’s major research interest is intestinal wound healing.
Impaired wound healing can lead to the development of inflammatory bowel diseases, poorer absorption of nutrients across the intestinal epithelium and other effects.
Five years ago, Kim Bak Jensen and colleagues discovered that the cells in the intestine revert to a fetal stage when they heal wounds.
The reason is that wound healing requires cells that can divide rapidly. Fetal cells are suited to this because they create a very long intestine during the brief fetal stage, and this requires almost exponential growth.
Conversely, fetal intestinal cells cannot function in the intestines of adults because mature cells are required. Mature intestinal cells can absorb nutrients from the environment and pass them through the intestinal epithelium into the bloodstream. They also act as a barrier against bacteria and viruses so that they cannot invade the body through the epithelium.
“We wanted to determine what distinguishes fetal intestinal cells from the mature intestinal cells of adults and what biochemically causes the cells to switch from one stage to the other,” says another researcher behind the project, Hjalte List Larsen, Assistant Professor, Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW, University of Copenhagen.
Two groups of proteins keep the cells in the fetal stage
In both studies, the researchers used three-dimensional cultures of cells from the intestines of fetuses and adults. Under these conditions, intestinal stem cells can grow as organoids (mini-organs) in the laboratory and retain the characteristics of the intestine of an adult or fetus.
This technology has enabled these new studies and has been a game-changer in stem cell biology.
The researchers used organoids to learn more about the cell stages.
In the first study, they investigated how the cell stages differ in epigenetics and transcriptional factors.
Epigenetics is a mechanism for modifying gene expression by folding the genetic material or attaching various molecules, which makes reading the genetic code easier or more difficult for the cell’s molecular machinery. The cell can thereby control transcriptional factors, which regulate the activity of genes encoded by the DNA and thereby the formation of proteins.
This part of the study showed that two groups of transcription factors AP1 and YAP/TEAD are essential for keeping cells in the fetal stage.
The YAP/TEAD factors are activated when cells lose contact with their neighbours, which can happen when the intestinal epithelium is damaged. This activates YAP, a protein that binds to the TEAD factors and thus activates transcription.
The cells then begin to produce the proteins normally present in the fetal stage.
YAP signals are important for wound healing
In the second study, the researchers used CRISPR technology to systematically delete various genes associated with the fetal stage, thus determining the effects of the individual genes in keeping cells in either an adult or fetal stage.
These experiments showed that two proteins from the epigenetic SWI/SNF complex are essential for keeping cells in the fetal stage. These proteins have a role in the YAP signalling pathway, which links the two studies.
Based on the results, the researchers suggest that the YAP signalling pathway is dominant in determining the identity of the cells, since both methods identified this as important for keeping the cells in the fetal stage.
“We hope that these studies have provided more insight into the properties of these stages and how to nudge cells in one direction or the other and thus potentially promote wound healing. Activating the YAP signalling pathway could perhaps promote wound healing because it nudges the cells towards the fetal stage in which they can more easily grow and repair the intestinal epithelium. But the cells must not be trapped in the fetal stage. We now also have an idea of how to nudge the cells out of this primitive stage and thus improve the protection of the intestine,” concludes Kim Bak Jensen.