A dying cell’s last act

When immune cells get sick, they will often self-destruct to protect the rest of the body from harm. New research suggests that before pulling the plug they send out final goodbyes, and even place a call to the undertaker.

Molecular biologist Georgia Atkin-Smith was peering through a microscope at a self-destructing cell when, to her surprise, she saw it releasing strings of bead-like structures before disintegrating completely.

Using time-lapse microscopy, Atkin-Smith and colleagues at La Trobe University in Melbourne, Australia, captured the event on video. The beads turned out to be packed with messenger molecules, the researchers report in the journal Nature Communications.

“They’ve discovered something nobody expected,” says John Silke, a biochemist at Melbourne’s Walter and Eliza Hall Institute of Medical Research. “Now it’d be really cool to see if this happens inside the body,” he adds.

Since English polymath Robert Hooke coined the term “cell” in 1665, we’ve learned a lot about the tiny structures that make up all living organisms. In the quest to learn more about life, some microscopists study death – such as when viruses take hold of immune cells.

Monocytes are the largest of all white blood cells. When you cut your finger, for example, the monocyte army senses a surge of microbes, and rush in to defend the body against the invaders. But if the monocytes come under attack – by becoming infected by a virus, say – they’ll fall on their own sword, a process known as apoptosis.

Apoptosis is a carefully choreographed event in which the cell packs up its own innards for recycling, before bulging, or “blebbing”, and rupturing into little capsules that get collected by the body’s undertakers, the macrophages, whose role includes clearing away dead cells. The cleanup needs to be meticulous. Some cellular contents, including the DNA from the nucleus, can trigger a damaging inflammatory response if left in the body.

Atkin-Smith studied monocyte cells in a petri dish, using intense flashes of UV light to activate their self-destruct mechanism. Using a time-lapse microscope, she took an image every two minutes over four hours, then stitched them together to create a video. After the cells blebbed, but before the blebs dispersed, she spied delicate tentacles shooting out from the cell surface.

Captured for the first time by La Trobe University researchers using time-lapse microscopy. Before the cells die they bubble or ‘bleb’ and shoot out strings of capsules containing molecular messages.CREDIT: LA TROBE UNIVERSITY

These “beaded apoptopodia” looked like strings of tiny pearls on a chain, each bead 10,000 times smaller than a real pearl. The strings eventually broke off and floated into the liquid and the cells around it. “I couldn’t believe it,” Atkin-Smith says. Previous researchers have not been interested in these last stages of cell death, which is why she believes the strings have not been seen before.

What are the strings for? Looking inside the beads, the team found molecules known to be involved in signalling. The researchers suspect the beads are a way for the dying cell to communicate with the rest of the body, like shooting a flare to warn nearby cells of a possible pathogen attack.

Immune cells have been shown to shoot out messages while under attack before – small bubble-like cellular structures called exosomes that possibly warn neighbouring cells to prepare for invasion. But exosomes bud off one at a time, whereas monocytes form beads, all roughly the same size, into long strings.

The experts agree the strings are too well-defined to be an evolutionary quirk. “After they bleb, cells are effectively dead. The question is: ‘Why are they so busy?’” asks Silke. “It’s hard to imagine that it’s not for a purpose.”

Silke believes the strings may also act as a snag: “They’ve got that look of something that might catch something.” Atkin-Smith agrees. Through the microscope, she’s seen the body’s clean-up macrophages grab on to the string of beads like a grappling hook, to draw the dying cell in and engulf it more easily. “It’s a really interesting thing and we’ve seen it a few times.”

So if the strings form late in the death process, what does it mean for the viruses inside the self-destructing cell?

Atkin-Smith is now looking into the possibility viruses use the released beads to hitch a ride to other cells. “Viruses can hijack everything else. I don’t see why they shouldn’t be able to hijack this as well,” says Paul Gleeson, molecular biologist at the University of Melbourne.

Atkin-Smith and her team have already shown they’re able to inhibit the formation of these strings of beads with certain drugs. If viruses are found to make use of the strings, the discovery could lead to a new family of anti-viral drugs.