Nav: Home

Cellular pumps protect the gut from toxins

August 26, 2018

The master regulators of gut stem cells, called intestinal myofibroblasts, have pumps that protect them, and thus the gut, from the toxic effects of a wide range of compounds, including the anticancer drug tamoxifen, according to 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, 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 of epithelial cells that live only three to five days, are continuously replaced, and can regenerate following injury. This continuous replacement is due to the presence of stem cells in crypts found within the intestinal lining. The cells surrounding these crypts provide a supportive microenvironment that controls stem cell function. Some of these supporting cells, including myofibroblasts, make signalling molecules called Wnt proteins. The proteins combine with receptors on stem cells to control the expression of genes involved in regulating stem cell proliferation and differentiation.

Wnt signalling also plays a role in promoting tumour growth, so there is much interest in developing drugs that inhibit it. But there is concern that doing so could be toxic to the gut by damaging the stem cell microenvironment. Surprisingly, compounds that inhibit the secretion of Wnt proteins, called PORCN inhibitors, have limited toxicity on the gut. Other compounds that inhibit Wnt signalling by acting directly on stem cells, on the other hand, are toxic.

Researchers at Duke-NUS Medical School in Singapore and international colleagues conducted experiments on mice and cultured cells and found that myofibroblasts were resistant to the toxic effects of a range of 'xenobiotics': foreign compounds that are not naturally produced by the body. This included resistance to drugs designed to inhibit Wnt secretion. The resistance was found to be due, at least in part, to the presence of specific 'drug efflux pumps', which can actively remove toxic compounds from within the cells. These pumps protect myofibroblasts when other intestinal cells might be affected, allowing 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," says Assistant Professor Babita Madan, the study's lead contact and a biochemist with the Cancer and Stem Cell Biology Programme.
-end-
Other researchers have found that similar cellular pumps within cancer cells can make people resistant to cancer treatments. Compounds that turn these pumps off could enhance their efficacy. Based on the current study, the Duke-NUS researchers and their colleagues caution these compounds might also be toxic to the intestine.

Reference: Chee, Y. C., Pahnke, J., Adsool, V. A., Madan, B., & Virshup, D. M. (2018). Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche. Developmental Cell.

Duke-NUS Medical School

Related Stem Cells Articles:

A protein that stem cells require could be a target in killing breast cancer cells
Researchers have identified a protein that must be present in order for mammary stem cells to perform their normal functions.
Approaching a decades-old goal: Making blood stem cells from patients' own cells
Researchers at Boston Children's Hospital have, for the first time, generated blood-forming stem cells in the lab using pluripotent stem cells, which can make virtually every cell type in the body.
New research finds novel method for generating airway cells from stem cells
Researchers have developed a new approach for growing and studying cells they hope one day will lead to curing lung diseases such as cystic fibrosis through 'personalized medicine.'
Mature heart muscle cells created in the laboratory from stem cells
Generating mature and viable heart muscle cells from human or other animal stem cells has proven difficult for biologists.
Mutations in bone cells can drive leukemia in neighboring stem cells
DNA mutations in bone cells that support blood development can drive leukemia formation in nearby blood stem cells.
Scientists take aging cardiac stem cells out of semiretirement to improve stem cell therapy
With age, the chromosomes of our cardiac stem cells compress as they move into a state of safe, semiretirement.
Purest yet liver-like cells generated from induced pluripotent stem cells
A team of researchers from the Medical University of South Carolina and elsewhere has found a better way to purify liver cells made from induced pluripotent stem cells.
Stem cell scientists discover genetic switch to increase supply of stem cells from cord blood
International stem cell scientists, co-led in Canada by Dr. John Dick and in the Netherlands by Dr.
Stem cells from diabetic patients coaxed to become insulin-secreting cells
Signaling a potential new approach to treating diabetes, researchers at Washington University School of Medicine in St.

Related Stem Cells Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#530 Why Aren't We Dead Yet?
We only notice our immune systems when they aren't working properly, or when they're under attack. How does our immune system understand what bits of us are us, and what bits are invading germs and viruses? How different are human immune systems from the immune systems of other creatures? And is the immune system so often the target of sketchy medical advice? Those questions and more, this week in our conversation with author Idan Ben-Barak about his book "Why Aren't We Dead Yet?: The Survivor’s Guide to the Immune System".