Two separate studies from Columbia University by Columbia scientists, published today in the journal Cell, suggest that for the past 15 years, researchers have been studying the wrong gut stem cells. Gut stem cells, the body’s unsung heroes, are in a constant state of activity. They tirelessly renew the cells lining our intestines, a process that involves replacing them roughly every four days. This remarkable feat occurs across a surface area that spans the size of a tennis court.
Understanding these hard-working stem cells might help scientists activate less efficient stem cells in other organs to repair hearts, lungs, brains, and more.
More than 15 years ago, gut stem cells were supposedly identified. However, using new tools, Columbia researchers Timothy Wang and Kelley Yan discovered that these cells are descendants of the natural gut stem cells. The stem cells are located differently, produce proteins, and respond to other signals.
The intestinal epithelium is a single-cell layer lining the gut. It is crucial for digesting food, absorbing nutrients, and fighting microbes. These cells live only about four days and need constant replacement by stem cells.
Remarkably, the intestinal lining is so large that if spread out, it would cover a tennis court. The gut’s stem cells might be the hardest working in the body.
Since 2007, it’s been believed that Lgr5, a protein, marks intestinal stem cells. All Lgr5+ cells were thought to be stem cells and vice versa, located at the bottom of intestinal crypts.
However, over the last decade, issues arose with this model. Removing Lgr5+ cells in mice didn’t affect the intestine much, and these cells reappeared in a week. Even after severe injury, the intestine regenerated without most Lgr5+ cells.
Stem cells are supposed to regenerate tissues, so this was puzzling. Some suggested that other mature cells could become stem cells again or that dormant stem cells were activated by damage. However, the simplest explanation that Lgr5+ cells aren’t stem cells was largely overlooked.
Researchers collaborated with Andrea Califano, who developed advanced algorithms to map cell relationships. Using single-cell RNA sequencing, we analyzed all cells in the intestinal crypts. They used these algorithms to find the source of “stemness.”
They discovered that stem cells are located in the isthmus region, not among the Lgr5+ cells. After removing Lgr5+ cells, we confirmed that isthmus cells could regenerate the intestinal lining. We found no evidence that mature cells could revert to stem cells.
The goal was to understand other cells involved in intestinal regeneration, not specifically to identify stem cells. Defining these other progenitor cells has been challenging.
Researchers found a proliferative group of cells marked by the protein FGFBP1. Computational analysis showed that these FGFBP1 cells give rise to all intestinal cells, including Lgr5+ cells, reversing the accepted model.
Claudia Capdevila, a graduate student, created a mouse to identify actual stem cells. In this mouse, when FGFBP1 was activated, cells expressed red and blue fluorescent proteins. Red appeared immediately and faded quickly, while blue appeared later and lasted longer.
Tracking these cells over time showed that FGFBP1 cells create Lgr5+ cells, not vice versa. This technique, called time-resolved fate mapping, demonstrated this reversal and was a significant achievement.
Researchers have been studying the wrong cells. Revisiting past studies with this new understanding could lead to better therapies for intestinal diseases and potential stem cell transplants in the future.
Researchers aim to find a universal pathway for stem cells so that they can be transferred to other tissues like skin, brain, heart, and more. Understanding actual stem cells could also help prevent cancers that arise from malfunctioning stem cells. That’s why it’s essential to identify the correct stem cells.
Journal reference:
- Claudia Capdevila, Jonathan Miller, et al., Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells. Cell. DOI: 10.1016/j.cell.2024.05.001.