New placenta model uses space-age technology

Channeling outer space, researchers at Magee-Womens Hospital have grown cells resembling those in the human placenta in March to study how infectious diseases lead to birth defects, especially the Zika virus.

The team, which also includes researchers from Johns Hopkins and Arizona State University, found that using NASA-engineered zero gravity technology, scientists can artificially grow cells that resemble those taken directly from a human placenta. The new technology allows cells to float together in spheres rather than forming a flat sheet in a Petri dish, according to the study, which was published in the journal Science Advances on March 4.

These cells fuse together, expressing genes related to pregnancy hormones and blocking the transmission of certain diseases, just like placental cells. Using powerful genetic tools, the researchers can dissect biochemical mechanisms underlying how the placenta functions as an organ of nutrient, gas and waste exchange and as a barrier to disease.

In the future, the model cells may help research infectious diseases that cross the placenta to cause birth defects, including the Zika virus, according to lead author Carolyn Coyne, associate professor of Microbiology and Molecular Genetics at Pitt and a member of the Magee Womens Research Institute.

Coyne said the system works by inducing shear, a force that pulls parallel surfaces of a cell in opposite directions, causing something shaped like a square to resemble a rhombus.

“Cells in the body, some more than others, are always sensing shear,” Coyne said. “Having these shear forces on the cells jogs their memory,” allowing them to differentiate into placental-like cells.

The researchers tested their new placental model in three different ways. They proved their cells looked like placental cells, secreted pregnancy hormones and resisted pathogens like placental cells do, Coyne said.

First, the model cells fused together and grew a dense forest of microvilli, tiny fingers about half a micron wide that facilitate nutrient, gas and waste exchange by increasing surface area, according to the study. These are the same physical characteristics of the placental cells bathed in maternal blood.

Second, the model cells excreted proper levels of the placental pregnancy hormones, including human chorionic gonadotropin and human placental lactogen, according to the study. Traditional cell cultures do not secrete these hormones, whereas cells taken from human placentas excrete pregnancy hormones at approximately the same level as the researchers’ new model.

Finally, the model demonstrated the same resistance to certain pathogens as placental cells. The pathogens tested so far include vesicular stomatitis virus, which, according to the U.S. Department of Agriculture, primarily affects livestock, and Toxoplasma gondii, the parasite often found in cat litter that causes toxoplasmosis and can lead to cognitive deficits, blindness and epilepsy if transmitted to the fetus, according to the Centers for Disease Control and Prevention.

Traditional cell cultures do not resist infection by VSV and T. gondii infection, whereas both the new model and cells derived from human placentas are highly resistant to both of these pathogens, according to the study.

Using this new model, Coyne and her team will study how the placenta resists disease transmission in most cases but fails in others.

“Now we have a system that fuses spontaneously and also a system that we can genetically manipulate, and then we can go back to answer some very basic questions that I think have been missing in the field,” Coyne said.

The placenta is normally very good at protecting the developing fetus from maternal infections. But it is critical to understand why sometimes pathogens cross that barrier to induce congenital disease, according to Coyne.

There are two possibilities: either the pathogen has changed or there is something about the host — that woman, that pregnancy, that placenta — that increases susceptibility.

These questions are particularly pertinent to the recent suggestion that Zika virus, a pathogen spread by mosquitoes, may cause birth defects.

In January 2016, an outbreak of Zika virus in Brazil coincided with a surge in microcephaly — a birth defect characterized by abnormally small heads and neurological impairments — and according to the CDC, mounting evidence shows that the virus can cross the placenta and attack fetal brain cells.

In February 2016, the World Health Organization declared Zika a public health emergency. Although much remains to be done in linking Zika to microcephaly, Coyne’s model could facilitate Zika research.

“My lab is working around the clock on Zika,” Coyne said, “trying to answer some of these early questions with the hope that at least we can provide a little bit of insight into what’s happening at the placental level.”

Before Zika was in the news, infectious disease was not something at the forefront of most pregnant women’s minds.

“I honestly never really thought about these things before,” said Megan Tomaino, a 31-year-old physician’s assistant at UPMC currently nine weeks pregnant with her second child.

Understanding disease transmission across the placenta is more important to expectant mothers than ever.

“Wow, I am worried about Zika,” Tomaino said. “I’m waiting to talk to the midwives [at Magee] about prevention, but I’m considering long sleeves this summer when I’m outside.”

Researchers must better characterize the behavior of the new cell model before it becomes widely used, said co-author Yoel Sadovsky, scientific director of Magee Womens Research Institute.

“Just because the cells differentiate does not mean that they will behave like [placental] cells in all aspects, like fighting viral infections.” Sadovsky said. “We’re trying now in our lab … to characterize what it takes for [placental] cells to resist viral infections.”

Coyne said clinical research could be difficult to manage in pregnant women, but she is optimistic about the model’s future and its benefits for expectant mothers.

The new model, which Coyne plans to continue testing, will allow her lab to uncover the basic biochemical mechanisms by which the placenta acts as both barrier and conduit between mother and child, and in particular how infectious agents can traverse the placenta to cause fetal damage.

“The pie in the sky … is that eventually it could lead to a better understanding that could be aimed at therapeutics,” Coyne said. “But I think that’s going to be really complicated. There is still much basic science to do first.”