Advancement in Fetal Growth Research: Potential Therapy Reverses Placental Development Issues in Mice

Tuesday, December 3, 2024

A signal that the body adds to an mRNA can disrupt placental development and lead to fetal growth restriction (FGR). In this condition, a fetus is smaller than expected for its age during pregnancy, and complications such as feeding difficulties, jaundice, and stillbirth can result. A molecule called STM2457 reversed most of the effects in mice and could someday be used treat patients, according to research published in The FASEB Journal.

FGR (also called intrauterine growth restriction) occurs in about 10% of pregnancies, and is diagnosed by measuring fundal height—the size of the maternal abdomen—or by performing an ultrasound. Maternal diabetes or high blood pressure, as well as placental issues or fetal genetic conditions can contribute to FGR. Treatments to fix the condition do not yet exist, so physicians carefully monitor these pregnancies, and they may induce labor early if fetuses aren’t developing properly. Stillbirth is a risk, as well as problems with breathing and feeding that can occur after birth. Because organs and tissues grow more slowly, children who experienced FGR in utero can have long-term cardiac, metabolic, and neurodevelopmental effects.

Reports have shown that the epigenetic modification N6-methyladenosine (m6A) on mRNA is associated with female reproductive diseases and pregnancy-related conditions, such as preeclampsia, gestational diabetes, and miscarriage, but it was unclear whether the modification is involved in FGR. 

As a first step toward developing a therapy for FGR, Guolin He, Xinghui Liu, and colleagues at West China Second University Hospital, Sichuan University, and Chongqing Medical University wanted to learn more about how the condition develops. They tested placental tissues from FGR patients and women with pregnancies that were proceeding as expected. The researchers also analyzed cells in culture and mice under various conditions.

The team found that m6A levels were higher in placental tissues of FGR patients than in those from control volunteers. METTL3 adds m6A to mRNAs, and its mRNA and protein levels were boosted in FGR patients. In laboratory experiments, increasing METTL3 expression elevated m6A, and knocking out METTL3 reduced m6A in two different cell lines derived from trophoblasts. In tests, trophoblasts with high METTL3 levels could not perform activities that are key to placenta formation, including proliferating, migrating, or moving into a material that mimics the environment around cells.

Further analyses revealed that METTL3’s likely target for these effects is an mRNA called FOSL1, which is encoded by a gene known to be involved in placental development. Adding m6A to FOSL1 mRNA makes it more stable, thereby boosting its protein levels. 

Next, the team wanted to test the effects of STM2457 on the m6A process. This molecule is a specific inhibitor of METTL3 and was recently shown to be a potential anticancer therapy. In an FGR mouse model, STM2457 treatment helped fetuses gain weight, partially restored placental development, and decreased m6A levels.

“This is the first study testing the therapeutic potential of STM2457 against FGR,” says He. “I think STM2457 can be a treatment, although the safety for its use in pregnancy requires further validation.”

Funding: National Key Research and Development Program of China, Sichuan Science and Technology Program

Read the full article, “METTL3 and IGF2BP2 coordinately regulate FOSL1 mRNA via m6A modification, suppressing trophoblast invasion and contributing to fetal growth restriction,” published in The FASEB Journal.