Intestinal myofibroblasts- the master regulators of the stem cells present in our gut, have pumps that protect them and consequently also the gut, from the toxic effects of several compounds, which also includes the anticancer drug tamoxifen, reports the findings of an investigation led by Duke-NUS Medical School.
“We have identified a unique population of cells that are master regulators of gut stem cells. These important support cells are uniquely protected from drugs and toxins in the diet,” explains Professor David Virshup, the director of Duke-NUS’ Cancer and Stem Cell Biology Research Programme and one of the study’s authors. “This allows you to take strong medicines and eat spicy foods without affecting your gut stem cell population. These master regulator cells are intrinsically drug resistant.”
The intestinal lining is made up of epithelial cells that survive only up to 3 to 5 days and are continuously replaced. They can also regenerate after an injury-which is because of the presence of stem cells in crypts that are found within the intestinal lining.
The cells that surround these crypts act as a supportive microenvironment that controls the function of stem cells. Some of these supporting cells, including the myofibroblasts make signalling molecules that are called Wnt proteins, which combine with receptors present on stem cells to control the expression of genes which are involved in regulating stem cell proliferation and differentiation.
Wnt signalling also tends to promote tumor growth, so it is especially important that drugs are developed to inhibit it. But doing so can result in toxins being exposed to the gut and thus damaging the stem cell microenvironment. But surprisingly these compounds that can inhibit the secretion of Wnt proteins- known as PORCN inhibitors, only have a limited toxicity on the gut. Other compounds that inhibit the Wnt signalling by directly acting on stem cells are usually toxic.
For the study, researchers at Duke-NUS Medical School in Singapore and international colleagues conducted experiments on mice and cultured cells and discovered that myofibroblasts were resitant to the toxic range of ‘xenobiotics’- which are foreign compounds that are not naturally produced by the body.
This also included resistance to drugs designed to inhibit Wnt secretion. The resistance was found to be a result of the presence of specific ‘drug efflux pumps’, which can actively get rid of toxic compounds from within the cells. These pumps protect myofibroblasts when other intestinal cells are affected, which allows them to continue the crucial Wnt signalling for intestinal regeneration.
“Xenobiotic resistance of the Wnt-producing myofibroblasts can protect the intestinal stem cell niche in the face of an unpredictable environment,” said the Assistant Professor Babita Madan, the study’s lead contact and a biochemist with the Cancer and Stem Cell Biology Programme.