Stem cells constantly adapt to their environment to maintain organ and tissue health, informed by chemical signals and physical forces. When they do not function as intended, stem cells can result in a number of health conditions including inflammatory bowel disease (IBD) and colorectal (bowel) cancer, where they continue to divide until a tumour forms.

Until now, how stem cells sense the physical forces around them has remained unclear, but novel findings in Science led by Dr. Meryem Baghdadi, a former SickKids postdoctoral researcher, Dr. Tae-Hee Kim at SickKids and Dr. Danijela Vignjevic at Institut Curie, has revealed that stem cells depend on two ion channels, called PIEZO1 and PIEZO2, for their survival.

“The physical properties of the environment around stem cells are crucial to our health,” explains Kim, Senior Scientist in the Developmental & Stem Cell Biology program. “With this knowledge, we can explore ways to promote gastrointestinal regeneration to not only prevent, but repair damaged stem cells.”

How stem cells sense changes in our gut

In 2018, Dr. Xi Huang, Senior Scientist in the Developmental & Stem Cell Biology program at SickKids, found that PIEZO ion channels influence tumour stiffening in brain cancer. Inspired by this research, Kim’s research team set out to explore how stem cells in the intestines use PIEZO channels to stay healthy and function properly.

In a preclinical model, the study team knocked out (turned off) PIEZO1 and PIEZO2 in the intestines. The results were dramatic: in the absence of both PIEZO channels, the stem cells couldn’t maintain their necessary functions, leading to severe illness and rapid death. Although these PIEZO channels were previously known to have distinct functions, this study has revealed their unexpected redundancy in stem cell maintenance.

The Kim and Vignjevic labs identified that PIEZO ion channels were helping stem cells feel physical changes in their surroundings, like how stiff or stretchy the environment is. Without these channels, there was an imbalance in two critical signaling pathways, causing the stem cells to miss important changes in their environment and improperly differentiate.

“When PIEZO channels are missing, stem cells can’t stay stem cells. Instead, they turn into other cell types too quickly, leading to serious health problems,” says Baghdadi.

The discovery has significant implications for human health, particularly for conditions with abnormal stem cell activity such as IBD, one of the fastest growing conditions in Canada, and bowel cancer, the third most common cancer in the country.

“More and more we are finding that our cells are more than just biology, there are chemical and mechanical signals which are driving cell activity,” says Kim. “How and why our body responds to these signals will open up new doors of research not just for gut health, but for every aspect of human health.”

This study was funded by the Canadian Institutes of Health Research (CIHR), the Labex Cell(n)Scale, the ARC Foundation and the European Research Council (ERC). The main authors also would like to thank the collaborators in Canada and Europe for their significant contributions.