MetalloGutRepair · Identification of a Metalloproteinase-17-mediated cellular signalling circuit in intestinal regeneration and tumorigenesis

Identification of a Metalloproteinase-17-mediated cellular signalling circuit in intestinal regeneration and tumorigenesis

Our digestive tract is continuously working to allow us to incorporate the water and the nutrients that our body needs, keeping pathogens, and possible threats under control. To do so, the intestinal surface is layered by a barrier named the intestinal epithelium. This barrier is bombarded with chemical, mechanical, and biological injuries daily. But, can resist and perform its absorptive role thanks to its high renewal rate. Cells are renewed by younger cells coming from the bottom part of structures called crypts in the epithelium. At the crypts, intestinal stem cells (ISCs), replicate themselves and give rise to daughter cells that will generate all the different epithelial cells (including cells that absorb nutrients, cells that produce mucus and cells that defend the intestine from pathogens). These ISCs need a proper environment to thrive and this is called the niche. The niche is a mix of factors, such as growth factors, fundamental in ISCs maintenance. When this niche is affected, the barrier is compromised and could lead to diseases as intestinal cancer, or impaired renewal after injury. One example of barrier dysfunction occurs in ulcerative colitis or in Chron’s disease (IBD, inflammatory bowel diseases). Still many aspects of the ISCs niche are unknown. Considering the importance of these factors in human diseases, we highlight the necessity to investigate it in more detail. Much has been uncovered about the role of epithelial cells in intestinal homeostasis, regeneration, and tumorigenesis, studied almost as a sole entity. In this work, we go a step forward and study other intestinal populations largely understudied, the intestinal muscle. The intestinal muscle is an autonomous musculature (smooth muscle) that is specifically located surrounding the epithelium. The upper part of this muscle is near the bottom of the crypts where the ISCs are located. So, we investigated the regulation of the intestinal epithelium by the muscle, under different circumstances, something that hasn’t been addressed in detail before. We demonstrated that this muscle has a fundamental role in regulating the ISCs niche. This role is so important that, when we removed a specific protein only present in the muscle, it results in a reduction of the ISCs number and therefore the reparative role of the intestinal barrier was compromised. Because of that, intestinal threats in mice lacking this protein resulted in injuries unable to heal and increased tumour generation. With these results, our objectives have been achieved. First, we proposed to establish the role of this protein in intestinal inflammation and regeneration. We know today that this protein is necessary during intestinal regeneration after diverse intestinal injuries. Second, we wanted to determine the role of this protein in intestinal tumorigenesis and we demonstrated that its protective against tumour generation, since mice lacking the protein developed a higher number of tumours. Our third objective was to identify the factors that interact with this protein. We have identified a substrate for this protein, that is implicated in intestinal cancers and found several factors that are produced by the muscle and regulate the intestinal epithelium. In sum, we have demonstrated the importance of the intestinal muscle as an ISCs niche provider, regulating the epithelial function, particularly during intestinal regeneration after injury. This investigation expands the knowledge on the intestinal healing process of crucial importance in human diseases as IBD, intestinal infections, and tumours.

Data: CORDIS, © European Union