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The intestine is highly susceptible to and affected by the harsh conditions caused by DNA-altering agents, such as radiation and chemotherapy, during cancer treatment. For example, many patients with tumors in the gastrointestinal cavity receive radiotherapy, a treatment that often also damages the healthy intestine and affects its ability to regenerate. That is why it is very important to have a good understanding of how the regeneration of the intestinal epithelium occurs, a key process about whose cellular and molecular mechanisms very little has been known until now.
Researchers at the National Cancer Research Center (CNIO) in Spain have now discovered one of the essential cellular and molecular mechanisms for the regeneration of the intestinal epithelium. It is a finding that lays the foundations to stimulate this process if it fails, and to preserve it in the face of radiotherapy or chemotherapy.
As the results of the new study show, what prompts the intestinal stem cells to regenerate the mucosa depends on the communication between different types of cells in the epithelial tissue. Researchers have also found a way to intervene in this communication, and thus improve regeneration.
The study is titled “Transit-amplifying cells control R-spondins in the mouse crypt to modulate intestinal stem 2 cell proliferation.” And it is published in the academic journal Journal of Experimental Medicine. It is led by the head of the CNIO Growth Factors, Nutrients and Cancer Group, Nabil Djouder, and has Almudena Chaves-Pérez and Karla Santos-de-Frutos as first authors.
Karla Santos-de-Frutos and Nabil Djouder in their laboratory. (Photo: Antonio Tabernero / CNIO)
The group has spent years investigating how to improve the regeneration of various organs —particularly the liver and the intestinal mucosa—, and thus mitigate the effects of radiotherapy. His findings in this period have been published in academic journals with a high impact index.
“The regeneration of the intestinal epithelium is very important in the functioning of the intestine”, explains Djouder. “Until now we knew that it is promoted by powerful mitogenic factors –proteins–, which stimulate the proliferation of intestinal stem cells; but we did not know how these factors are regulated”.
The current study indicates that –unexpectedly for the researchers– it is the progenitor cells involved in regenerating the epithelial mucosa that modulate the production of mitogenic factors. The process is as follows: when severe damage occurs, stem cell injury leads to tissue inflammation; this stops the production of mitogenic factors and, consequently, the proliferation of stem cells and the consequent regeneration of the mucosa.
“For us, this communication between at least four different cell types is new: the progenitor cells, which differentiate to form the epithelial mucosa; the cells that secrete the mitogenic factors; inflammatory cells; and the intestinal stem cells themselves,” says Djouder. “This communication must be very well controlled, so that the tissue responds adequately to aggression.”
“That progenitor cells communicate with inflammatory cells and coordinate the rate of proliferation of intestinal stem cells is fascinating,” he adds.
Djouder places special emphasis on the new role that progenitor cells have been observed to have: “Our study suggests that progenitor cells are not simple bystanders in the process of epithelial regeneration, but rather play an active and highly important role in decisions made by intestinal stem cells in regeneration. The progenitor cells explain to the intestinal stem cells when and how to divide, and therefore control their self-regeneration”.
“This study has allowed us to better understand cell cooperation, in order to open doors to reduce adverse effects in traditional cancer treatments”, say Chaves-Pérez and Santos-de-Frutos, first authors of this work.
The group has also confirmed results observed in previous works: the c-MYC oncogene plays a fundamental role in regeneration. Due to the damage produced by the radiation, and the increase of c-MYC in the progenitor cells, inflammation in the intestine increases and the levels of mitogenic proteins are reduced; however, by removing or inhibiting c-MYC, the process is reversed: inflammation is reduced, mitogenic factors are increased, and intestinal regeneration is improved during severe damage.
“Our data show an unexpected role of progenitor cells in the control of inflammatory signals and the production of mitogenic factors, essential to maintain the proliferation of intestinal stem cells and tissue regeneration”, explain the authors of the study.
The finding, they say, opens a new path in research on how to counteract the side effects of genotoxic agents such as radiation or chemotherapy used during the treatment of gastrointestinal cancer. (Source: CNIO)
