Flatworms reveal explosive new type of immune cell
In Brief:
Stanford scientists discovered a new type of cytotoxic cell called “ruptoblasts” in experiments with planarian flatworms.
Unlike common blood-derived immune cells, ruptoblasts are specialized gland cells that undergo an explosive cell death called "ruptosis” when triggered by a specific hormone.
A single ruptoblast can kill dozens of target cells within minutes through an explosion of toxic agents that quickly dissipate.
Ruptosis is the most explosive form of cell death known to date, making it distinct from all previously described cell death pathways.
Stanford scientists have discovered a new type of immune cell that kills surrounding cells via explosion – a cellular detonation so fast and complete that the cell vanishes within minutes, leaving no trace behind. This discovery comes from an unlikely source: planarian flatworms. These aquatic, slithering pancake versions of worms are famous for their ability to survive dismemberment and grow whole new organisms from the sliced-up segments of their formerly unified body. Understanding how these flatworms’ immune systems have managed to endure for hundreds of millions of years could hold important insights for modern medicine.
In a new study published June 2 in Cell, the team describes the discovery and names these new cells “ruptoblasts” for their explosive response to a certain hormone.
“We never expected that a cell could just explode like a bomb and kill the cells surrounding it,” said senior author Bo Wang, associate professor of bioengineering in the schools of Engineering and Medicine.
Flatworm inflammation
Chew Chai, a postdoctoral researcher in the Wang lab, first observed these cells while investigating the long-standing mystery in flatworm biology of whether or not they can tell the difference between their own tissues and those of another individual. To find out, she longitudinally sliced the flatworms and fused them together with a separate worm. Although adept at regrowing their own tissues, Chai noted that these “Frankenstein” worms rejected halves of other worms, similar to how a human body may reject an organ transplant from a donor.
Unlike humans, however, a different cellular defense mechanism sprang into action.
“It’s this huge inflammatory response. Like there’s a fire and an alarm goes off, and the cells just blow up,” said Chai, who is lead author of the paper.
Through previous studies of flatworms’ regeneration abilities, scientists know that levels of the hormone activin play a key role in their survival. High levels of activin are known to reduce a flatworm’s ability to regrow its body, while low levels inhibit their ability to reproduce with other worms. When Chai noticed the worms rejecting the tissues of another worm, she also observed a spike in activin levels and subsequent chronic inflammation. The flatworms did not immediately perish from this inflammation, but died within a few days. Chai also observed that injecting otherwise healthy, nonfused flatworms with activin triggered a similar level of inflammation.
Looking into this response on the cellular level required Chai to use live-cell microscopy and flow cytometry – a laser-based analysis technique. She stained cells with different fluorescent dyes, then sorted individual cells to isolate those that responded to activin exposure. A subset of these cells burst open and spewed contents that killed surrounding cells, then vanished within five minutes of the explosion. Chai and Wang call this response “ruptosis.”
The swift and complete self-destruction of these ruptoblast cells is one aspect that makes them so unique from other forms of cell death.
“Some mammalian cells and bacteria may also do an explosive sort of cell death, but the timescale is really long. They are exploding, but it’s more like pores that slowly leak things out over the course of several hours,” said Chai. “Ruptosis happens within seconds to minutes.”
An ancient evolutionary solution
In a matchup against E. coli bacteria, human kidney cells, and mouse blood cells, ruptoblasts destroyed all three. Yet the authors noted that cell fatalities were limited to the immediate area of the explosion and did not trigger any sort of chain reaction or lingering toxicity. This localized effect, Wang says, holds promise for targeted treatments of bacterial infections or tumors.
Another characteristic that sets ruptoblasts apart from other immune cells, like T-cells or neutrophils, is the fact that they are glandular cells rather than hematopoietic cells, or blood cells produced in the bone marrow. The ruptoblasts seem to figure out a way to amplify their secretion machinery to suddenly and violently release cytotoxic substances in response to activin. A sharp increase in calcium from the endoplasmic reticulum within the ruptoblast helps facilitate the ruptosis.
In searching for these cells in other organisms, Chai discovered that they only appear in basal bilaterians like the flatworms, which points to these cells having early evolutionary origins. Chai wonders if the reason these cells were filtered out of modern vertebrate immune systems is because vertebrates lack the ability to repair other cells after ruptosis occurs, unlike flatworms that are rich in stem cells.
“It demonstrates there’s lots of different immune mechanisms out there. There’s all these animals that live in an environment where there’s lots of bacteria, lots of viruses, and we know so little about their immune mechanisms,” said Wang.
These findings point out how much value strange, seemingly simplistic creatures like flatworms can add to the study of immune responses. Looking outside of traditional model organisms, Wang said, can inspire new strategies and innovative solutions for some of the most difficult medical problems.
Acknowledgements
Additional Stanford co-authors include postdoctoral scholar Souradeep Sarkar; former Undergraduate Visiting Research Program scholar Lihan Zhong; Dania Nanes Sarfati, PhD ’24; Christine Jacobs-Wagner, the Dennis Cunningham Professor and professor of biology in the School of Humanities and Sciences and of microbiology and immunology in the School of Medicine; and Hawa Racine Thiam, assistant professor of bioengineering in the schools of Engineering and Medicine and of microbiology and immunology in the School of Medicine. Additional co-authors, including co-senior author Benyamin Rosental, are from Ben Gurion University of the Negev.
Jacobs-Wagner is also a member of Stanford Bio-X and an institute scholar at Sarafan ChEM-H. Thiam is also a member of Bio-X and the Maternal & Child Health Research Institute (MCHRI), and an institute scholar at Sarafan ChEM-H. Wang is also a member of Bio-X and the Wu Tsai Neurosciences Institute.
This research was funded by a National Science Foundation Graduate Research Fellowship, a Stanford Graduate Fellowship, a Stanford DARE fellowship, a Human Frontier Science Program grant, a National Institutes of Health grant, and the European Research Council.
Journal
Cell
Article Title
Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense
Article Publication Date
2-Jun-2026
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