'Mini placentas' in a dish reveal key gene for pregnancy

An enzyme made famous by the COVID-19 pandemic plays an unsung role in healthy placenta development during pregnancy, according to a new study.

The enzyme, called angiotensin-converting enzyme 2 (ACE2), can be exploited by the novel coronavirus as a doorway into human cells. However, outside the context of COVID, ACE2 plays important roles in human health — including during pregnancy.

Broadly, ACE2 is part of a system that helps regulate blood pressure and fluid levels in the body. In this system, ACE2 helps widen blood vessels and triggers anti-inflammatory responses while its counterpart, angiotensin-converting enzyme (ACE), boosts cell and tissue growth.

In past studies, different versions of the ACE2 gene have been tied to pregnancy complications, such as preeclampsia, which can cause high blood pressure and liver and kidney problems during or after pregnancy, as well as babies being small for their gestational age.

These problems have also been tied to issues with the placenta, which provides oxygen and nutrients to the fetus, but the role ACE2 plays in the placenta hadn't yet been clarified.

Now, in a new study, scientists found that tweaking the gene for ACE2, or knocking it out entirely, causes lab-grown models of the placenta to end up smaller and less symmetrical. The findings, reported Feb. 7 in the journal Cell Death and Disease, shed light on the role of ACE2 in pregnancy and could help scientists develop treatments for complications related to the gene and its activity.

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"By having [a specific variant in the ACE2 gene], you're 23 times more likely to have a small-for-gestational-age baby," study coauthor Anya Arthurs, a molecular biologist at Flinders University in Australia, told Live Science. "I'd seen this statistic, but no one had actually looked at why that happened."

Arthurs and her colleagues used stem cells collected from donated placental tissue to grow organoids — small, simplified versions of placentas that can be grown in lab dishes. They grew some organoids with the normal ACE2 gene and others without it; plus, they edited a third group to swap one building block in the gene for out for another at a key site. In this way, they made the third group of miniature placentas carry the ACE2 variant that's known to be associated with small-for-gestational-age babies.

These edits to the genome enabled the team to study how changes to the ACE2 gene would affect placental development.

Both the organoids that lacked the ACE2 gene and the ones with the edited gene grew more slowly and were less symmetrical than the organoids with the normal gene, the scientists found. The ratio of ACE2 to ACE proteins was also higher in the edited organoids than in the normal organoids, while the ones that lacked the ACE2 gene didn't produce any ACE2 proteins at all.

Together, these results suggest that disrupting the typical ratio of these key proteins could somehow affect placenta growth and development for the worse.

"It's really important that these two sides of the system exist in a balance in a tissue," Arthurs said. "If you have only one, you're going to have problems — too invasive, too inflammatory." With too much ACE, cells might grow out of control like they do in cancer.

"And if you have too much of this ACE2 anti-inflammatory, anti-proliferative pathway, you're not going to have a successful pregnancy because the placenta is not going to be able to form the way it should," Arthurs suggested.

The study is the first to explore gene editing in a human placental organoid as a way to investigate the molecular causes of pregnancy disorders. Researchers could use the technique to study other pregnancy complications, such as gestational hypertension, said Gloria Valdés, a researcher at the Pontifical Catholic University of Chile, who was not involved in the research.

"The field that the paper has opened is extremely interesting," Valdes told Live Science.

Arthurs is now studying placental organoids that mimic a preeclamptic placenta, which releases molecules that can go on to affect kidney and liver function. Better understanding the placenta's role in the disease could point to potential treatments.

"I think it's important to know the molecular mechanisms which underpin a pathology," Arthurs said. "If you don't know the molecular mechanism, you can't design a therapy."