The outer layer of cells (thin ring above) in a several-days-old human embryo goes on to form the placenta.

ANDY WALKER/MIDLAND FERTILITY SERVICES/SCIENCE SOURCE

The placenta—a Frisbee-size hunk of tissue that chaperones a fetus in the uterus only to be tossed aside in the delivery room—has mysterious beginnings. The organ emerges from cells that develop alongside the embryo, and that have been difficult to grow in the lab. Now, researchers have devised a way to derive and observe early precursors of placental cells in a dish. They have found a method of “reprogramming” adult cells, reverting them to a primitive state, that can prompt them to become trophoblast stem cells (TSCs), which give rise to placental cells.

The method promises a window on how defects in placental development may lead to infertility, miscarriage, and preeclampsia, a dangerous complication of pregnancy. “It’s like gaining a toehold on Mars,” says reproductive biologist Susan Fisher at the University of California, San Francisco. “We know almost nothing about the early steps.”

Those steps begin just days after a sperm and egg join. “The first decision in human life is to set aside the placental, supportive cells,” says Kathy Niakan, a developmental biologist at the Francis Crick Institute, whose team reported key molecular signals for that initial step in Nature last week. These cells go on to form the trophoblast, a multilayered ring that surrounds the embryo and helps it implant into the wall of the uterus. Some of these cells, TSCs, then give rise to cell types that will make up the bulk of the placenta, which enables mother and fetus to exchange nutrients and gases and helps protect the fetus from the mother’s immune system.

Scientists have derived TSC-like cells from unused embryos created for in vitro fertilization (IVF) or from the placentas of terminated pregnancies, but both are limited resources. And in a dish, these cells have tended to mature and stop dividing. The same has been true of TSC-like cells created from cultured embryonic stem (ES) cells and from induced pluripotent stem (iPS) cells—mature cells reprogrammed to an ESlike state.

But in 2017, Tohoku University stem cell biologist Takahiro Arima and colleagues described a broth of nutrients and other compounds that could make TSCs from IVF embryos or first trimester placentas thrive in a dish. “An enormous amount of work that was never possible before became possible,” says William Pastor, a stem cell biologist at McGill University. This year, Pastor’s group and two others showed this culture medium could also coax certain types of ES cells to become self-renewing TSCs.

To make TSCs that genetically match a patient, however, researchers want to be able to start from mature skin or blood cells. In the two new studies, teams led by stem cell biologists Jose Polo at Monash University and Laurent David at the University of Nantes found ways to convert adult skin cells into “induced” TSCs. Both teams had been studying how gene expression changes as mature cells are reprogrammed into iPS cells. They noticed that along the way, some expressed genetic signatures of so-called trophectoderm cells, which give rise to the trophoblast.

“That was very weird,” Polo says, because a cell’s decision to become trophectoderm happens so early in development—not anywhere along the expected path backward from skin cell to iPS cell. But by culturing the cells in the newly available medium, the researchers managed to push them to become TSCs.

In a 16 September Nature paper, Polo’s team reported that these induced TSCs could develop into two major types of trophoblast cells and, like the cells surrounding an embryo, secrete human chorionic gonadotropin, a hormone whose signals are key to maintaining a pregnancy. David, a co-author on that paper, separately used gene expression data from human embryos to estimate that his own group’s lab-derived TSCs are equivalent to those seen 8 to 10 days after fertilization, the team reported on 15 September in a preprint on bioRxiv.

It will be important to thoroughly compare these induced TSCs to placenta-derived and ES cell–derived TSCs, says Washington University in St. Louis stem cell biologist Thorold Theunissen, whose team recently derived TSCs from ES cells. That analysis should include comparing the chemical tags on DNA that influence cell function and sizing up how efficiently the cells differentiate into different types of specialized trophoblast cells.

Induced TSCs could now be used to study genetic defects that can end a pregnancy, says Soumen Paul, a stem cell biologist at the University of Kansas Medical Center. By making TSCs from cells from women with infertility and watching them develop in the lab, researchers could pinpoint how abnormal trophoblast cells prevent the embryo from implanting in the uterus or from developing normally once implanted.

Or TSCs could help root out causes of preeclampsia, in which a pregnant woman suddenly develops high blood pressure that sometimes can be relieved only by inducing an early delivery. Preeclampsia is thought to stem from a defect of the placenta, perhaps in the way it invades the uterine wall and interacts with the mother’s blood vessels, Pastor says. Researchers should now be able to make TSCs from umbilical cord blood or from a baby’s blood or skin cells to observe how placental precursor cells emerge and interact with uterine cells.

The new TSCs could also add realism to synthetic embryo models—stem cell–derived structures that mimic early human development in a lab dish. So far, they haven’t included trophoblast or other such “extra-embryonic” cells, says Jianping Fu, a bioengineer developing such models at the University of Michigan, Ann Arbor. But signals from these cells are critical to normal embryo growth, he says. Adding them would take the models “to the next level.”

Better approximations of real embryos will raise ethical concerns. The U.S. National Institutes of Health has not released formal guidelines, but Fu says the agency discouraged him from including trophoblast tissue in a recent grant application. But he thinks such experiments should proceed. “When you mix the cells together, allowing them to self-organize … they will do amazing things.”



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