Like chickens, duck-billed platypuses, and other animals that hatch from eggs, you had a yolk sac when you were an embryo. For many vertebrates, this pouch serves multiple developmental roles, including holding, well, yolk, the nutrient-rich liquid that helps nourish the embryo.
However, the function of the human yolk sac is unclear. It contains no yolk and dwindles during the second trimester of pregnancy—the placenta instead provides the key route for feeding the offspring. Now, a study out in Science today reveals the human yolk sac stands in for organs such as the liver and kidneys that arise later in development. The findings could help researchers create better embryo mimics in the lab and devise new ways to cultivate immune cells for treating diseases.
There’s been “a dearth of studies on the human yolk sac,” says developmental biologist Anthony Carter of the University of Southern Denmark, who wasn’t connected to the research. The new work, he says, “is a huge breakthrough in terms of getting data” about what happens in the first few weeks after conception.
Although the yolk sac never produces its namesake substance in most mammals, it’s not vestigial. In mice, the yolk sac manufactures the embryo’s first blood cells and relays nutritious molecules produced by the uterus. And in some tissues of adult rodents, the immune cells known as macrophages are descended from yolk sac cells, not the bone marrow cells that give rise to most macrophages.
But researchers haven’t been able to pin down whether the yolk sac performs similar or other roles in human embryos, in part because it’s difficult for them to acquire the relevant tissue samples, which come from embryos donated after abortions. Some studies have suggested that, as in mice, the human structure produces primordial blood cells for the embryo, but the results weren’t conclusive, says Sarah Teichmann, an immunologist at the Wellcome Sanger Institute and co-author of the new paper. “The human evidence was kind of fuzzy.”
To delve deeper into the structure’s capabilities, Teichmann, along with Wellcome immunogenomicist Muzlifah Haniffa and colleagues, obtained samples of human yolk sac tissue from a biobank in the United Kingdom. The samples came from embryos that were 4 weeks to 8 weeks old. Next, the researchers profiled gene activity in the tissues, looking to identify which cells were present and what they were doing.
The data confirmed that a human embryo also makes its first blood cells in the yolk sac. Only 4 weeks after conception, the structure harbored blood-forming stem cells, macrophages, and other kinds of circulatory system cells, the team reports. As development progresses, the yolk sac hands over this job to the forming liver, which then passes it to the bone marrow, the birthplace of blood cells in adults.
As in other species, the human yolk sac is a multitasker, the study shows. It also carries proteins for breaking down harmful toxins and produces proteins necessary for blood clotting—a key ability in the early embryo. Several enzymes in the human structure take part in lipid and sugar metabolism, a discovery that implies that despite lacking yolk, the sac still provides nourishment. “We have to assume that [the enzymes] are synthesizing molecules that support the embryo,” Teichmann says.
The more the scientists looked, the more possible functions they found. Adults’ kidneys churn out erythropoietin, a hormone that stimulates formation of new red blood cells, and the yolk sac appears to be the early embryo’s source for the substance. Forming red blood cells is “very important” during development, Carter says.
The team also discovered that the yolk sac uses an unexpected shortcut to produce macrophages. As one of these immune cells matures, it usually goes through an intermediate stage known as a monocyte, but the yolk sac macrophages bypass this step. Learning how to replicate this route in lab dishes could make it easier to raise macrophage cells in culture, the authors say, which could help researchers who are trying to harness the cells for treating cancer and repairing damaged tissues. The scientists also tested whether, like in mice, yolk sac–derived macrophages are still present in adult tissues. Preliminary findings hint that they are.
What the results of the study show, Haniffa says, is that “there is a fleeting structure during early development that is absolutely critical for the embryo.” The versatile yolk sac “is three organs in one,” she says, performing jobs that will later be delegated to the liver, kidneys, and bone marrow.
Researchers have produced embryolike clumps of cells for probing early development, and the study’s results could help scientists make these simulated embryos more lifelike, Haniffa and Teichmann add. One challenge of using such mimics is that they stop developing at early stages, but ensuring that the yolk sac is present may allow them to progress further.
Whether the human yolk sac takes on other tasks—in some species, for example, it transfers maternal antibodies to embryos—remains to be seen. Still, Carter says, “It’s exciting that we have this little organ early on that has so many jobs.”
