Stanford researchers have discovered a previously unknown immune cell in planarian flatworms that destroys nearby cells by rapidly exploding. The process, called ruptosis, occurs within seconds to minutes and leaves almost no trace of the cell.
The discovery was made in planarian flatworms, small aquatic animals famous for their remarkable ability to regenerate. Even after being cut into pieces, these animals can rebuild missing body parts and, in some cases, develop into complete organisms. Understanding how their immune systems evolved and functioned over hundreds of millions of years could provide new insights for medicine and biotechnology.
In a study published in Cell, the researchers named the newly identified immune cells ruptoblasts. The name refers to the explosive way these cells respond to the hormone activin.
“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 Stanford University’s schools of Engineering and Medicine.
Flatworms Reject Foreign Tissue
Chew Chai, a postdoctoral researcher in Wang’s laboratory and lead author of the study, discovered the unusual cells while investigating whether flatworms can recognize and reject tissue from another individual.
To explore this question, Chai cut flatworms lengthwise and fused each animal with tissue from a different worm. Although flatworms are highly effective at rebuilding their own bodies, the fused “Frankenstein” worms rejected tissue from unrelated individuals. The response was similar in some ways to the rejection of a transplanted organ by the human immune system.
The cellular reaction, however, was unlike typical immune responses observed in humans.
“It’s this huge inflammatory response. Like there’s a fire and an alarm goes off, and the cells just blow up,” Chai said.
Activin Triggers Explosive Inflammation
Earlier studies of flatworm regeneration found that the hormone activin plays an important role in survival and reproduction. High levels of activin can impair regeneration, while low levels can interfere with the animals’ ability to reproduce with other worms.
As the fused worms began rejecting foreign tissue, Chai observed rising activin levels followed by persistent inflammation. The animals did not die immediately, but they died within several days. Injecting activin into healthy, unfused flatworms produced a similar inflammatory response.
To study the response at the cellular level, Chai used live-cell microscopy and flow cytometry, a laser-based method for analyzing and separating cells. The researchers labeled cells with fluorescent dyes and isolated those that responded to activin.
A small population of cells suddenly burst open, released substances that killed nearby cells, and disappeared in less than five minutes. Chai and Wang named this rapid form of cell death ruptosis.
Ruptoblasts Die Within Seconds
The speed and completeness of ruptoblast destruction set ruptosis apart from other known forms of programmed or explosive 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,” Chai said. “Ruptosis happens within seconds to minutes.”
This rapid process effectively turns each ruptoblast into a localized biological weapon. Instead of gradually releasing potentially harmful material, the cell releases its contents almost instantaneously.
Explosive Immune Cells Destroy Multiple Targets
In laboratory tests, ruptoblasts destroyed E. coli bacteria, human kidney cells, and mouse blood cells. The findings suggest that these cells can attack both pathogens and animal cells.
The damage remained concentrated near each ruptoblast explosion. Researchers did not observe a spreading chain reaction or lasting toxicity. According to Wang, this combination of powerful activity and precise localization could eventually inform new strategies for treating bacterial infections or targeting tumors.
Ruptoblasts are also fundamentally different from well-known immune cells such as T cells and neutrophils. T cells and neutrophils are hematopoietic cells, meaning they develop from blood-forming cells in bone marrow. Ruptoblasts, by contrast, are glandular cells.
The researchers believe ruptoblasts may amplify their normal secretion machinery, allowing them to release toxic substances suddenly after detecting activin. A rapid increase in calcium from the endoplasmic reticulum, an internal structure within the cell, appears to help trigger ruptosis.
An Ancient Immune Defense
When Chai searched for similar cells in other species, she found them only in basal bilaterians, including flatworms. Their limited distribution suggests that ruptoblasts may represent an ancient immune strategy that emerged early in animal evolution.
Chai proposed that vertebrates may have lost this defense because they cannot readily repair the surrounding tissue damage caused by ruptosis. Flatworms, however, possess abundant stem cells and can replace injured tissues with exceptional efficiency.
“It demonstrates there’s lots of different immune mechanisms out there. There are 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,” Wang said.
The findings highlight the scientific value of studying animals that are not commonly used as traditional research models. Although flatworms may appear simple, their regenerative abilities and unusual immune cells could reveal biological strategies that are not found in humans or other vertebrates.
Wang said that examining a broader range of organisms could inspire new approaches to some of medicine’s most difficult challenges, including infectious disease and cancer.
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), as well as an institute scholar at Sarafan ChEM-H. Wang is also a member of Bio-X and the Wu Tsai Neurosciences Institute.
This research was supported 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.
Source: www.sciencedaily.com