Scientists discover neuron-like communication system in the gut

In a key advance for regenerative medicine and gut health, scientists from Duke-NUS Medical School and Nanyang Technological University, Singapore (NTU Singapore) have uncovered a precise and unexpected communication system in the gut. Support cells known as telocytes use fine extensions-like neurons in the brain-to deliver signals directly to intestinal stem cells. Their study, published in the journal Developmental Cell, challenges long-standing assumptions about how the gut maintains and repairs itself, possibly leading to better treatments for conditions like IBD and colon cancer.

The intestinal lining is one of the most active tissues in the human body. It renews itself every few days, thanks to a small group of stem cells that live deep within tiny pockets found in the gut lining, called crypts. These stem cells divide and specialize, becoming the different types of cells needed to keep the gut healthy and functional. To accomplish this differentiation of cells, the stem cells rely on instructions from surrounding support cells in the stem cell niche-the specialised microenvironment in which stem cells live and function.

Until recently, scientists thought that these special chemical signals, called Wnts, floated freely through the surrounding tissue, eventually reaching the stem cells via diffusion. This offered a partial explanation of how stem cells are regulated, but did not explain how such a random process would ensure that messages arrived at exactly the right time and place when needed.

Professor David Virshup, Director of the Programme in Cancer and Stem Cell Biology at Duke-NUS Medical School and co-corresponding author of the study, explained: "We discovered that these signals aren't just drifting through tissue. They're being delivered with surprising precision from the niche to the stem cells by specialized cells or telocytes-changing the way we think about cellular communication in the gut, similar to how neurons pass signals to one another in the brain."

Telocytes are especially interesting due to their ability to send out long, thin extensions called cytonemes. These filaments reach directly from the telocyte to a specific stem cell. Using advanced imaging techniques, including high-resolution fluorescence and electron microscopy, the team observed that telocytes in the mouse intestine use cytonemes to deliver Wnts directly to individual stem cells in the crypt.

This neuron-like behavior in gut cells upends our understanding of how organs maintain themselves-making this one of the clearest cellular analogues between brain and gut function seen to date.

The researchers also found that the contact points between the telocyte and stem cell are similar in appearance to synapses, the one-to-one connections between nerve cells. This precise form of communication makes it possible to transport Wnts directly to their intended location.

"This kind of direct, cell-to-cell communication highlights a new level of precision in how secreted molecules are delivered to their target cell." said Assistant Professor Alexander Ludwig from the School of Biological Sciences at NTU Singapore, one of the authors of the study. "It's a striking example of how imaging at different scales coupled with new protein tagging approaches can uncover novel mechanisms and change paradigms."

To better understand how this communication system works, the scientists investigated the nuts and bolts of the telocytes, the proteins that scaffold for the cytonemes. When these proteins, specifically two key players named KANK and Liprin, were disrupted, the cytonemes failed to form or function correctly, and the special Wnt transport machinery failed to function.

Principal Research Scientist Dr. Gediminas Greicius, from Duke-NUS' Programme in Cancer and Stem Cell Biology and first author of the study, said the discovery highlights the power of exploring fundamental biology.

Sometimes when you study the basics closely, you uncover something transformative. This system of targeted signaling was hiding in plain sight, and now that we see it, it reshapes our understanding of the biology of stem cells in the gut."

Dr. Gediminas Greicius, from Duke-NUS' Programme in Cancer and Stem Cell Biology

While the research focused on healthy tissue, the implications are far-reaching. Disruptions in Wnt signalling are already known to drive some form of colon cancer. Similarly, impaired signalling may play a role in chronic inflammatory bowel disease (IBD) like Crohn's disease and ulcerative colitis-conditions that are increasingly common in Singapore and the region.

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, noted the broader importance of the discovery.

"This discovery could change how we approach tissue repair and regenerative medicine," said Professor Tan. "If we can harness or restore this precise mode of signaling, it may enhance the effectiveness of stem cell therapies and help develop more targeted treatments for gut-related diseases. It's a strong example of how basic science drives real-world impact."