New research shows a tiny, regenerative worm could change our understanding of healing

KANSAS CITY, MO — October 15, 2025 — Stem cells in most organisms typically take cues from adjacent cells. But new research from the Stowers Institute for Medical Research reveals planarian stem cells ignore their nearest neighbors and instead respond to signals further away in the body. This discovery may help explain the flatworm’s extraordinary ability to regenerate — and could offer clues for developing new ways to replace or repair tissues in humans.

The study, published in Cell Reports on October 15, 2025, and led by Postdoctoral Research Associate Frederick “Biff” Mann, Ph.D., from the lab of Stowers President and Chief Scientific Officer Alejandro Sánchez Alvarado, Ph.D., challenges the textbook concept that most stem cells reside in a fixed, physical place called a niche, where surrounding cells tell them when or when not 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.

The team, however, revealed that the planarian’s remarkable ability to regrow body parts, for example, rebuilding an amputated head or even an entire body from just a tiny fragment, is linked to stem cells that act more independently from their surroundings 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 have unlimited potential to become any type of cell, in contrast to most other organisms including humans whose stem cells are tightly regulated to enable them to produce just a few specialized cell types. Part of this control system is in place to help prevent unchecked cell growth, which is a hallmark of 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’,” said 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.”

Armed with the emerging technology of spatial transcriptomics, the researchers could determine which genes are turned on not just within one cell but also within surrounding cells in a tissue. This revealed surprising neighbors — notable varieties of cell types that surround stem cells. The most prominent was one not previously characterized — a very large cell with a multitude of projections, or fingerlike extensions of its cell membrane. The team named these cells “hecatonoblasts” after Hecatoncheires, a Greek mythological monster with many arms.

“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, the team discovered the strongest instructions came from intestinal cells — the next most prominent cell type in their dataset. They found these cells were indeed providing planarian stem cells with instructions regarding their position and function during regeneration, despite being a considerable distance away.

“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.”  

The team discovered that planarian stem cells seem to be uncoupled from traditional contact-based niches and “found that there isn’t a specific cell type or factor right next to stem cells that is controlling their identity,” said Benham-Pyle. Thus, they hypothesize that this may be the key underlying planarian stem cell potency, and the incredible regenerative feats flatworms can perform.

“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.

About the Stowers Institute for Medical Research

Founded in 1994 through the generosity of Jim Stowers, founder of American Century Investments, and his wife, Virginia, the Stowers Institute for Medical Research is a non-profit, biomedical research organization with a focus on foundational research. Its mission is to expand our understanding of the secrets of life and improve life’s quality through innovative approaches to the causes, treatment, and prevention of diseases.

The Institute consists of 20 independent research programs. Of the approximately 500 members, over 370 are scientific staff that include principal investigators, technology center directors, postdoctoral scientists, graduate students, and technical support staff. Learn more about the Institute at www.stowers.org and about its graduate program at www.stowers.org/gradschool.

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