Columbia University’s research has uncovered a longstanding error in identifying gut stem cells, finding the true stem cells in a different site, which could revolutionize regenerative medicine by applying these findings to other organs.
Two independent studies by Columbia scientists suggest that research into the gut’s stem cells over the past 15 years has been marred by a case of mistaken identity: Scientists have been studying the wrong cell.
Both studies were published in the journal Cell. The gut’s stem cells are some of the hardest-working stem cells in the body. They work continuously throughout our lives to replenish the short-lived cells that line our intestines. About every four days, these cells—covering a surface about the size of a tennis court—are completely replaced.
Understanding these workaholic stem cells could help scientists turn on less productive stem cells in other organs to repair hearts, lungs, brains, and more. The gut’s stem cells were supposedly identified more than 15 years ago in a landmark study.
But using new lineage tracing and computational tools, the Columbia teams, led by Timothy Wang and Kelley Yan, found that these cells are descendants of the gut’s true stem cells. The gut’s true stem cells are found in a different location, produce different proteins, and respond to different signals.
“The new work is controversial and paradigm-shifting but could revitalize the [entire?] field of regenerative medicine,” says Timothy Wang, the Dorothy L. and Daniel H. Silberberg Professor of Medicine.
“We know we’re making a lot of waves in the field, but if we’re going to make progress, we need to identify the true stem cells so we can target these cells for therapies,” says Kelley Yan, the Herbert Irving Assistant Professor of Medicine.
We recently spoke with Kelley Yan and Timothy Wang about the findings and implications.
Why does the gut need stem cells?
KY: What’s relevant to this story is a tissue called the intestinal epithelium. This is a single layer of cells that lines the gut and it’s composed of different types of cells that help digest food, absorb nutrients, and fight microbes.
Most of the cells live for only about four days before being replaced, so stem cells must create replacements.
What’s really remarkable about the intestinal lining is how big it is. If we were to fillet open your intestine and lay it flat, it would cover the surface of a tennis court.
The gut’s stem cells may be the hardest-working stem cells in the body.
The gut’s stem cells were supposedly identified in 2007, and the discovery was hailed as a breakthrough in stem cell science. What made you think this was a case of mistaken identity?
TW: For the last 17 years, the intestinal stem cell field has assumed that Lgr5, a protein on the cell’s surface, is a specific marker for intestinal stem cells. In other words, all Lgr5+ cells are assumed to be stem cells, and all stem cells are believed to be Lgr5+. These Lgr5+ cells were located at the very bottom of glands, or crypts, in the intestinal lining.
However, in the last decade, problems with this model began to appear. Deleting the Lgr5+ cells in mice, using a genetic approach, did not seem to bother the intestine very much, and the Lgr5+ stem cells reappeared over the course of a week. In addition, the intestine was able to regenerate after severe injury, such as radiation-induced damage, even though the injury destroyed nearly all Lgr5+ cells.
KY: By their very definition, stem cells are the cells that regenerate tissues, so these findings created a paradox. Many high-profile papers have evoked different mechanisms to explain the paradox: Some suggest that other fully mature intestinal cells can walk backward in developmental time and regain stem cell characteristics. Others suggest there’s a dormant population of stem cells that only works when the lining is damaged.
No one has really examined the idea that maybe the Lgr5+ cells really aren’t truly stem cells, which is the simplest explanation.
How did your labs identify the gut’s real stem cells?
TW: My lab collaborated with the former chair of Columbia’s systems biology department, Andrea Califano, who has developed cutting-edge computational algorithms that can reconstruct the relationships among cells within a tissue. We used single-cell RNA sequencing to characterize all the cells in the crypts, the region of the intestine where the stem cells are known to reside, and then fed that data into the algorithms.
These algorithms revealed the source of “stemness” in the intestine not in the Lgr5+ cellular pool but in another type of cell higher up in the crypts in a region known as the isthmus. After eliminating Lgr5+ cells with radiation or genetic ablation, we confirmed these isthmus cells were the gut’s stem cells and able to regenerate the intestinal lining. We didn’t find any evidence that other, mature cells could turn back time and become stem cells.
KY: We weren’t trying to identify the stem cells as much as we were trying to understand the other cells in the intestine involved in the regeneration of the lining. No one has been able to define these other progenitor cells in the intestine.
We identified a population of cells that were proliferative and marked by a protein called FGFBP1. When we asked how these cells were related to Lgr5+ cells, our computational analysis told us that these FGFBP1 cells give rise to all the intestinal cells, including Lgr5+, the opposite of the accepted model.
My graduate student, Claudia Capdevila, then made a mouse that would allow us to determine which cells—Lgr5+ or FGFBP1+—were the true stem cells. In this mouse, every time the FGFBP1 gene is turned on in a cell, the cell would express two different fluorescent proteins, red and blue. The red would turn on immediately and turn off immediately, while the blue came on a little later and lingered for days.
That allowed us to track the cells over time, and it clearly showed that the FGFBP1 cells create the Lgr5+ cells, the opposite of what people currently believe. This technique, called time-resolved fate mapping, has only been used a few times before, and getting it to work was a pretty incredible achievement, I thought.
How will this affect the stem cell field and the search for stem cell therapies?
TW: This case of mistaken identity may explain why regenerative medicine has not lived up to its promise. We’ve been looking at the wrong cells.
Past studies will need to be reinterpreted in light of the stem cells’ new identity, but eventually it may lead to therapies that help the intestine regenerate in people with intestinal diseases and possible transplantation of stem cells in the future.
KY: Ultimately, we hope to identify a universal pathway that underlies how stem cells work, so we can then apply the principles we learn about the gut to other tissues like skin, hair, brain, heart, lung, kidney, liver, etc.
It’s also thought that some cancers arise from stem cells that have gone awry. So, in understanding the identity of the stem cell, we might be able to also develop novel therapeutics that can prevent the development of cancer.
That’s why it’s so critical to understand what cell underlies all of this.
References: “Time-resolved fate mapping identifies the intestinal upper crypt zone as an origin of Lgr5+ crypt base columnar cells” by Claudia Capdevila, Jonathan Miller, Liang Cheng, Adam Kornberg, Joel J. George, Hyeonjeong Lee, Theo Botella, Christine S. Moon, John W. Murray, Stephanie Lam, Ruben I. Calderon, Ermanno Malagola, Gary Whelan, Chyuan-Sheng Lin, Arnold Han, Timothy C. Wang, Peter A. Sims and Kelley S. Yan, , Cell.
DOI: 10.1016/j.cell.2024.05.001
“Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury” by Ermanno Malagola, Alessandro Vasciaveo, Yosuke Ochiai, Woosook Kim, Biyun Zheng, Luca Zanella, Alexander L.E. Wang, Moritz Middelhoff, Henrik Nienhüser, Lu Deng, Feijing Wu, Quin T. Waterbury, Bryana Belin, Jonathan LaBella, Leah B. Zamechek, Melissa H. Wong, Linheng Li, Chandan Guha, Chia-Wei Cheng, Kelley S. Yan, Andrea Califano and Timothy C. Wang, , Cell.
DOI: 10.1016/j.cell.2024.05.004
News
How the FDA opens the door to risky chemicals in America’s food supply
Lining the shelves of American supermarkets are food products with chemicals linked to health concerns. To a great extent, the FDA allows food companies to determine for themselves whether their ingredients and additives are [...]
Superbug crisis could get worse, killing nearly 40 million people by 2050
The number of lives lost around the world due to infections that are resistant to the medications intended to treat them could increase nearly 70% by 2050, a new study projects, further showing the [...]
How Can Nanomaterials Be Programmed for Different Applications?
Nanomaterials are no longer just small—they are becoming smart. Across fields like medicine, electronics, energy, and materials science, researchers are now programming nanomaterials to behave in intentional, responsive ways. These advanced materials are designed [...]
Microplastics Are Invading Our Arteries, and It Could Be Increasing Your Risk of Stroke
Higher levels of micronanoplastics were found in carotid artery plaque, especially in people with stroke symptoms, suggesting a potential new risk factor. People with plaque buildup in the arteries of their neck have been [...]
Gene-editing therapy shows early success in fighting advanced gastrointestinal cancers
Researchers at the University of Minnesota have completed a first-in-human clinical trial testing a CRISPR/Cas9 gene-editing technique to help the immune system fight advanced gastrointestinal (GI) cancers. The results, recently published in The Lancet Oncology, show encouraging [...]
Engineered extracellular vesicles facilitate delivery of advanced medicines
Graphic abstract of the development of VEDIC and VFIC systems for high efficiency intracellular protein delivery in vitro and in vivo. Credit: Nature Communications (2025). DOI: 10.1038/s41467-025-59377-y. https://www.nature.com/articles/s41467-025-59377-y Researchers at Karolinska Institutet have developed a technique [...]
Brain-computer interface allows paralyzed users to customize their sense of touch
University of Pittsburgh School of Medicine scientists are one step closer to developing a brain-computer interface, or BCI, that allows people with tetraplegia to restore their lost sense of touch. While exploring a digitally [...]
Scientists Flip a Gut Virus “Kill Switch” – Expose a Hidden Threat in Antibiotic Treatment
Scientists have long known that bacteriophages, viruses that infect bacteria, live in our gut, but exactly what they do has remained elusive. Researchers developed a clever mouse model that can temporarily eliminate these phages [...]
Enhanced Antibacterial Polylactic Acid-Curcumin Nanofibers for Wound Dressing
Background Wound healing is a complex physiological process that can be compromised by infection and impaired tissue regeneration. Conventional dressings, typically made from natural fibers such as cotton or linen, offer limited functionality. Nanofiber [...]
Global Nanomaterial Regulation: A Country-by-Country Comparison
Nanomaterials are materials with at least one dimension smaller than 100 nanometres (about 100,000 times thinner than a human hair). Because of their tiny size, they have unique properties that can be useful in [...]
Pandemic Potential: Scientists Discover 3 Hotspots of Deadly Emerging Disease in the US
Virginia Tech researchers discovered six new rodent carriers of hantavirus and identified U.S. hotspots, highlighting the virus’s adaptability and the impact of climate and ecology on its spread. Hantavirus recently drew public attention following reports [...]
Studies detail high rates of long COVID among healthcare, dental workers
Researchers have estimated approximately 8% of Americas have ever experienced long COVID, or lasting symptoms, following an acute COVID-19 infection. Now two recent international studies suggest that the percentage is much higher among healthcare workers [...]
Melting Arctic Ice May Unleash Ancient Deadly Diseases, Scientists Warn
Melting Arctic ice increases human and animal interactions, raising the risk of infectious disease spread. Researchers urge early intervention and surveillance. Climate change is opening new pathways for the spread of infectious diseases such [...]
Scientists May Have Found a Secret Weapon To Stop Pancreatic Cancer Before It Starts
Researchers at Cold Spring Harbor Laboratory have found that blocking the FGFR2 and EGFR genes can stop early-stage pancreatic cancer from progressing, offering a promising path toward prevention. Pancreatic cancer is expected to become [...]
Breakthrough Drug Restores Vision: Researchers Successfully Reverse Retinal Damage
Blocking the PROX1 protein allowed KAIST researchers to regenerate damaged retinas and restore vision in mice. Vision is one of the most important human senses, yet more than 300 million people around the world are at [...]
Differentiating cancerous and healthy cells through motion analysis
Researchers from Tokyo Metropolitan University have found that the motion of unlabeled cells can be used to tell whether they are cancerous or healthy. They observed malignant fibrosarcoma [...]
