If we could listen to stem cells closely enough, we might hear them whisper, “mechanosenses tingling.” After all, stem cells sense and react to the physical forces around them, maintaining their potency or pursuing one developmental fate or another. We might even say that stem cells have superpowers. But unlike the powers of a cartoon superhero, the mechanosensory powers of stem cells have real-world consequences. For example, if these mechanosensory powers fail, stem cells can malfunction, giving rise to health conditions such as inflammatory bowel disease (IBD) and colorectal cancer.
With so much at stake, we need a proper understanding of the relationship between stem cells and mechanical signals. “Proper” as in full of physical details. To acquire such details, scientists affiliated with the Hospital for Sick Children (SickKids) and Institut Curie looked into the intestinal stem cell (ISC) niche. Specifically, they studied the mechanosensitive signaling receptors known as PIEZO1 and PIEZO2. These receptors are ion channels that open in response to mechanical stimuli, allowing calcium to flow into the cell, activating downstream signaling pathways.
Essentially, the scientists decided to see what would happen if intestinal stem cells in a preclinical model were denied their PIEZO1 and PIEZO2 powers. When the scientists knocked out PIEZO1 and PIEZO2, 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.
Detailed findings appeared in Science, in a paper titled, “PIEZO-dependent mechanosensing is essential for intestinal stem cell fate decision and maintenance.”
“In vivo measurement of basement membrane stiffness showed that ISCs reside in a more rigid microenvironment at the bottom of the crypt,” the article’s authors wrote. “Three-dimensional and two-dimensional organoid systems combined with bioengineered substrates and a stretching device revealed that PIEZO channels sense extracellular mechanical stimuli to modulate ISC function.”
The paper’s first author is Meryem Baghdadi, PhD, a former researcher at SickKids, and the paper’s senior authors are Tae-Hee Kim, PhD, a senior scientist at SickKids, and Danijela Vignjevic, PhD, a research director at Institut Curie. The study they led expanded on the work of one of the paper’s co-authors, Xi Huang, PhD, a senior scientist at SickKids.
In 2018, Huang found that PIEZO ion channels influence tumor stiffening in brain cancer. Inspired by this research, the collaborators in the current study set out to explore how stem cells in the intestines use PIEZO channels to stay healthy and function properly.
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,” Baghdadi said.
The discovery has significant implications for human health, particularly for conditions with abnormal stem cell activity such as IBD.
“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,” Kim remarked. “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.”
“The physical properties of the environment around stem cells are crucial to our health,” Kim added. “With this knowledge, we can explore ways to promote gastrointestinal regeneration to not only prevent, but repair damaged stem cells.”
