In most animals, stem cells rely on nearby cells to tell them what to do. However, new research from the Stowers Institute for Medical Research shows that flatworm, or planarian, stem cells behave differently. Instead of listening to their immediate neighbors, they take their instructions from cells located farther away in the body. This surprising behavior may explain how flatworms can regrow missing parts so effectively and could reveal new ways to repair or replace human tissues in the future.
The findings, published in Cell Reports on October 15, 2025, come from a study led by Postdoctoral Research Associate Frederick "Biff" Mann, Ph.D., in the laboratory of Stowers President and Chief Scientific Officer Alejandro Sánchez Alvarado, Ph.D. The work challenges a long-held biological principle: that most stem cells live in a fixed "niche," a physical location where neighboring cells dictate when to divide and what to become.
"For instance, human blood-forming stem cells reside in niches within bone marrow where they divide to self-renew and make new blood cells," said Mann.
Flatworms Rewrite the Rules of Regeneration
The researchers discovered that flatworms' extraordinary ability to rebuild lost parts -- whether an amputated head or an entire body from a fragment -- is tied to stem cells that operate more freely than those in most other animals.
"Understanding how stem cells are regulated in living organisms is one of the great challenges in the fields of stem cell biology and regenerative medicine," said Sánchez Alvarado. "This finding challenges our concept of a stem cell 'niche' and may significantly advance our understanding of how to control stem cells' abilities to restore damaged tissues."
Adult planarian stem cells can transform into any type of cell, unlike most animals' stem cells, which are carefully restricted to forming only a few cell types. That tight control helps prevent uncontrolled growth -- a process that can lead to cancer.
"Our hope is to uncover the basic rules that guide stem cells to become specific tissues as opposed to going rogue, as most tumors in humans begin when stem cells stop following these rules," said Sánchez Alvarado.
"The role of a traditional niche may be more in line with a micromanager -- instructing cells, 'You can be a stem cell, but only one particular type'," explained Mann. "However, we've now shown having a normal niche may not be essential for stem cells to work. Some stem cells, like those in the planarian flatworm, have figured out a way to be independent and can turn into any type of cell without needing a nearby niche."
Discovering a New Cell Type: The Hecatonoblast
Using an advanced technique called spatial transcriptomics, the team examined which genes were active in individual cells and their surroundings. This revealed unexpected neighboring cells, including one never described before -- a large cell with many fingerlike projections extending from its surface. The researchers named these cells "hecatonoblasts," after Hecatoncheires, a many-armed giant from Greek mythology.
"Because they were located so close to stem cells, we were surprised to find that hecatonoblasts were not controlling their fate nor function, which is counterintuitive to a typical stem cell-niche connection," said Mann.
Instead of nearby cells taking charge, the strongest instructions for the stem cells came from intestinal cells -- the next most common type found in the dataset. These distant cells appeared to influence the planarian stem cells' position and function during regeneration, even from afar.
"I tend to think about this as local versus global communication networks," said co-corresponding author Blair Benham-Pyle, Ph.D., an Assistant Professor at the Baylor College of Medicine in Houston, Texas, and former Stowers Postdoctoral Research Associate. "While interactions between stem cells and their neighboring cells influence how a stem cell reacts immediately, distant interactions may control how that same stem cell responds to big changes in an organism."
Rethinking the Nature of a Stem Cell Niche
The research revealed that planarian stem cells operate without a fixed, contact-based niche. "We found that there isn't a specific cell type or factor right next to stem cells that is controlling their identity," said Benham-Pyle. The team believes this unique independence may explain why planarians can regenerate so completely when most animals cannot.
"The big discovery is a property of the whole planarian permitting both subtle local interactions and global signaling events that allow stem cells to achieve these remarkable feats of regeneration," said Benham-Pyle.
"The most surprising finding is that, at least in planarians, the environment in which the stem cells reside is not fixed. Instead, it's dynamic -- where stem cells reside is essentially made up by 'friends' that the stem cells and their progeny make along the way to differentiation," said Sánchez Alvarado. "The more we understand how nearby cells and overall signals in the body work together to boost the ability and power of our stem cells, the better we'll be at creating ways to improve the body's natural healing. This knowledge could help develop new treatments and regenerative therapies for humans in the future."
Additional authors include Carolyn Brewster, Ph.D., Dung Vuu, Riley Galton, Ph.D., Enya Dewars, Mol Mir, Carlos Guerrero-Hernández, Jason Morrison, Mary KcKinney, Ph.D., Lucinda Maddera, Kate Hall, Seth Malloy, Shiyuan Chen, Brian Slaughter, Ph.D., Sean McKinney, Ph.D., Stephanie Nowotarski, Ph.D., and Anoja Perera.
This work was funded by the National Institute for General Medical Sciences of the National Institutes of Health (NIH) (award: R37GM057260) and by institutional support from the Stowers Institute for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
