In the testicles of the fruit fly, murder is occurring on a massive scale. The victims: perfectly innocent and viable cells. The perp: phagocytes, a family of immune cells that had been thought (in our naivete) to focus on dead cells or, in the circulatory system, sick ones, and to encase and vanquish invasive micro-organisms.
The study, “The phagocytic cyst cells in Drosophila testis eliminate germ cell progenitors via phagoptosis,” by Profs. Hila Toledano, Estee Kurant of the University of Haifa and colleagues, appeared this week in Science Advances.
What are the perfectly viable cells being assassinated in the gonads of the fruit fly? Sperm precursors, about 25 percent of them.
Murder? Oh yes. “During spermatogenesis, phagocytes execute excessive live germ cell progenitors without any evidential provocation,” the authors write – the poor cells did nothing wrong, they are normal, insofar as we can tell. We will return to that point.
We will add here that the fruit fly, Drosophila melanogaster, has extraordinarily long sperm – 2 millimeters long, which is roughly how long the fly is, LiveScience reported in 2019. The evolutionary logic of that, we do not know. This is irrelevant to the point, but it’s good to know. Now back to the new paper.
Our cells are not immortal, but what governs their passage from this vale of tears? Cell death in general is suicide, Toledano explains. It is self-inflicted. Something inside the cell tells it: it’s time to die. And after the cell has died, a phagocyte eats and digests it.
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“Phagocytes are like the body’s ZAKA team, evacuating dead bodies,” she says. “In recent years, it also became clear that they play a function in clearing away [other white blood] cells that aren’t dead yet but their functionality is over. For instance, they may have swallowed viruses.”
But phagocytes had not been suspected of targeting perfectly healthy cells such as newly formed spermatogonial cells in the testicle. Yet they do. Why would they do that?
In the beginning
We all begin as embryonic stem cells, a blob of undifferentiated primordial cells that divide and generate differentiated tissue cells – brain, heart, nerve, skin, etc., thus creating the whole organism. Adults have no primordial embryonic stem cells, but our various tissues all have differentiated “adult stem cells” that generate new cells when the sick ones die.
In other words, the adult stem cells constantly replenish our tissues when our cells commit suicide. In this process, each adult stem cell first divides into two: one stem cell, and one differentiated one that replaces the dead cell in the tissue.
The fruit fly’s testes contain spermatagonial stem cells. Think of them as progenitor cells that produce the sperm. These spermatagonial cells divide, producing one other stem cell and one that turns into sperm.
But for years, science has been bedeviled by a mystery. About 25 percent of newly formed spermatagonial stem cells die in the fruit fly, in other insects, and in mammals too – rats and mice, for instance. “It had been thought that this was due to suicide, for reasons unknown,” Toledano says. In other words, the otherwise normal cells made that internal “decision” to die. “Now we show they’re murdered, eaten alive by the phagocytes. Cellular ceviche.”
What an appealing image that is.
Normal cells that kick their own bucket over exhibit phosphatidylserine (PS) “eat-me” signals on their exterior. But in this case, the researchers showed that in the fly, the progenitor germ cells are “spontaneously removed” – eaten by the phagocytes, without significant PS signals on their exterior.
When eating another cell, the phagocyte envelopes it and acidifies its interior (like they turn into mini-stomachs). Once they are done with the meal, they burp out the remnants in a sort of bubble.
The image below shows a microscopic immunofluorescent image of fruit fly gonadal tissue assassinating live cells. The red are the dead cells and the color, red, is indicative of high acidity. The green cells are the murderers, Toledano explains.
Why was this studied in fruit flies? Because they are extremely well known to science, they proliferate like crazy and there are no protests for fruit-fly rights. We know their genetics, we know their propensities and we know, she explains, which stem cells in their testicles are the progenitors. Genetic manipulation of the animals is also easy.
It is true that research on a tiny fly with giant sperm does not necessarily translate into meaning for mammals, but we do all have many molecular mechanisms in common, as the researchers point out.
Let us leave aside the methodology except to note that the researchers did prove that the cells are being swallowed by phagocytes, not suffering some other unspeakable fate; and also, real-time imaging of live tissue showed that the progenitor cells are being eaten alive by the phagocyte, and only then the death process is initiated, the authors say.
The million-sperm-count question is: Why would phagocytes consume and dissolve about a quarter of all sperm-cell progenitors in the fruit fly, the rat, and probably in men too? What might be the evolutionary advantage?
The answer must of course remain in the realm of speculation. It seems random, though possibly the doomed spermatogonial cells have some form of genetic damage and we don’t know what the signal is. But an intriguing hint, says Toledano, is that this form of cell murder increases when the fruit fly is starved.
In other words, a few (well, 25 percent) are sacrificed for the greater good of the fruit fly and its tissues, which need the nutrients provided by the digestion of the formerly healthy cells, she suggests.
Could this research have real-world application? Theoretically, the more we know about cell death, the more we may understand the development of cancer and how to get these murderous phagocytes to eat tumor cells.