Cellular Reprogramming fuels wound healing in the intestine

Bloody diarrhoea, stomach pain and discomfort. These are some of the symptoms experienced by patients suffering from inflammatory bowel disease. Patients with ulcerative colitis, a sub-type of inflammatory bowel disease, suffer from large wounds in the gut, which do not heal as usual. Today the condition is treated with drugs mainly targeting inflammation. Due to our poor understanding of wound healing at the cellular level, no existing treatment supports the intestines’ natural ability to heal the bleeding wounds. Now a large international collaboration headed by researchers from the Biotech Research & Innovation Centre (BRIC) at the University of Copenhagen has identified the mechanism that controls wound healing in the intestine.  

’We know that the intestine in healthy individuals is able to heal itself. We therefore reckoned that we need to understand normal wound healing before we can understand what goes wrong in patients with wounds that never heal. Here it is necessary to examine the normal process at the molecular level. We will subsequently be able to use this knowledge to potentially improve the wound healing process. Our new study shows that the healing depends on changes in the intestinal epithelial cells, where they are reprogrammed to a foetal-like state’, says Associate Professor and Head of the Research Group Kim B. Jensen from BRIC at the University of Copenhagen.

Two Proteins Are Vital to Wound Healing
The intestine contains a protective layer of cells, so-called epithelial cells. These cells create a barrier, which prevents the billions of intestinal bacterial found in the intestines from spreading to the rest of the body. If the epithelial barrier is damaged substances (bacteria and food remains) in the lumen will spread to the rest of the body causing immune reactions including inflammation. At worst, the inflammation may cause even more cells in the protective layer to die, and the patient will develop chronic ulceration. It is now up to the remaining epithelial cells to repair the damages and heal the wound, but this is a constant battle between the remaining epithelial cells and the inflammation.

In this study the researchers used mice with a chemically induced colitis to map the molecular process that directs wound healing in the epithelial cells. Their results demonstrated that the epithelial cells initiate wound healing by responding to changes in their neighbourhood. This leads to activation of two proteins YAP and TAZ, which causes dramatic changes in the epithelial cells, which fuels the wound healing process. Upon activation of YAP and TAZ the cells no longer look like cells in the normal epithelium, but are instead reprogrammed to a foetal-like state. Here they resemble the cells that participate in forming the bowel in the growing foetus. Once in this foetal state, the epithelial cells rapidly rebuild the damage.

’We know from previous studies that the foetal epithelial cells are very different from the cells in intestine, once it is fully formed. We also know that the two proteins YAP and TAZ are important to the wound healing process. With this study we have managed to show why YAP and TAZ are so important, and why the foetal-like state is critical to effective wound healing. The next step in our research is to learn precisely what the proteins do, as this will enable us to establish a brand new model for treatment. We hope that our research in the future will help patients with inflammatory bowel disease by facilitating better, faster and more effective wound healing’, says Kim B. Jensen.

The study has just been published in Cell Stem Cell and is available here. The study was conducted in close cooperation with Luca Azzolin and Stefano Piccolo at the University of Padova in Italy and researchers in Japan, the UK, Sweden and at Herlev Hospital.

Information About the Research Team
The international team behind the scientific results is headed by Kim Jensen, BRIC. The work was mainly conducted by Shiro Yui, a Japanese doctor specialising in enteritis. During the past four years Dr Yui has worked at BRIC, UCPH, financed by both Danish and EU funds. He is now back in Japan, where he supplements his research with clinical practice. In addition to Dr Yui, Luca Azzolin and Stefano Piccolo from the University of Padova in Italy and researchers from Japan, the UK, Sweden and at Herlev Hospital also participated in the project.

The project was funded by the Lundbeck Foundation, the Independent Research Fund Denmark’s Mobilex programme and the EU Horizon 2020 research and innovation programme under grant numbers 668294, 682665 and 670126, among others.

Contact:
Head of the Research Group Kim B. Jensen, kim.jensen@bric.ku.dk

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