Scripps Research team identifies sugar molecules that trigger placental formation

(Press-News.org) LA JOLLA, CA—During the first weeks of pregnancy, the developing placenta in a mother’s womb undergoes a dramatic change. Individual cells  merge, forming a continuous barrier that will spend the next nine months ferrying oxygen and nutrients to the growing fetus while keeping the mother's immune system at bay. When this structure fails to form properly, pregnancies are at higher risk of complications, including preeclampsia and restricted fetal growth.

Now, scientists at Scripps Research have identified a key player in the placenta’s transformation—a molecule called galectin-3 that binds to sugar molecules on specific cell surface proteins, likely holding placental cells tightly together to fuse.

The research, published in Proceedings of the National Academy of Sciences on November 4, 2025, not only illuminates an important mechanism in placental development but also demonstrates the power of a new technique for mapping the fleeting interactions between proteins and sugars.

“We were able to really zoom in and show that one protein and its sugar modification is critical for the biology of the placenta,” says senior author Mia Huang, professor of chemistry at Scripps Research. “This gives us new fundamental insight into placental biology and eventually could have implications for preventing or treating pregnancy complications.”

The placenta is vital to pregnancy, acting as the exchange site where oxygen and nutrients pass from mother to fetus and waste products are removed. But the precise molecular mechanisms that build this critical organ have been unclear. Previous studies had shown correlations between levels of galectin-3 and pregnancy complications, but scientists weren’t sure exactly what galectin-3 was doing in the placenta.

Proteins on cell surfaces are often decorated with complex sugar chains—modifications that help cells communicate and recognize each other. Galectin-3 is what's known as a glycan-binding protein, meaning it specifically recognizes and attaches to certain patterns of those sugar chains.

Huang’s lab turned to a technique they first used in 2020 to map out which sugar-decorated proteins galectin-3 recognizes. Called proximity labeling, the approach acts like molecular spray paint; when galectin-3 binds to a protein, molecules generated by a derivatized galectin-3 irreversibly tag proteins in the area. Then, scientists can work backward from the highlighted parts of the protein to find galectin-3’s exact binding site.  

In the new study, Huang and colleagues used proximity labeling to map galectin-3 binding in lab-grown cells derived from human placental tissue. Two proteins stood out that galectin-3 consistently attached to: CD9 and integrin beta 1 (ITGB1). When the researchers removed either protein from placental cells, the cells no longer fused during placental development. Then, when they investigated which specific sites on the CD9 protein galectin-3 was binding to, the team discovered an unconventional glycosylation site.

“It was really exciting to find such a rare glycosylation sequence,” says first author Abigail Reeves, a Scripps Research graduate student in Huang’s lab. “It really underscores how little we know about this kind of glycosylation. We can’t predict with absolute certainty what sugars will decorate a protein and which glycan binding proteins will recognize this modification.”

The team also showed that galectin-3 molecules need to cluster together to drive cell fusion. When they engineered galectin-3 to be unable to cluster, the placental cells no longer fused.

“We think what's happening is galectin-3 is binding to these CD9 glycoproteins at the cell surface and pulling them all together, creating this giant rigid structure,” explains Huang. The process takes about 48 hours, and the membrane clustering ultimately triggers the cells to fuse, the data suggest.

The new study adds to growing evidence that individual interactions between proteins and sugar chains can have large effects on cell function, Huang adds.

The researchers are now working to confirm whether the process occurs in developing human placentas, rather than isolated cell lines. That insight could eventually point toward new ways of preventing pregnancy complications by mediating galectin-3. The team also plans to apply proximity labeling to other types of cells to continue studying the role of protein-sugar interactions in human biology.

In addition to Huang and Reeves, authors of the study, “Mapping the placental galectin-3 interactome identifies CD9 and ITGB1 as functional glycoprotein counter-receptors during syncytialization,” include Gil-Suk Yang, Sabyasachi Baboo, Jolene Diedrich, Pranali Bedekar, Christopher Bratcher, and John Yates III of Scripps Research; and Shaheen Farhadi, Arun Wanchoo, and Gregory Hudalla of University of Florida.

This work was supported by funding from the Burroughs Wellcome Foundation, the National Science Foundation Graduate Research Fellowship Program (NSF GRFP, NSF/DGE-2235200), a Skaggs Graduate Fellowship from the Schimmel Family Foundation, the National Institutes of Health (R35GM142462, UM1AI144462, R01/R56AI113867) and the Conrad Prebys Foundation Research Heroes Program.

About Scripps Research

Scripps Research is an independent, nonprofit biomedical research institute ranked one of the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr-Skaggs, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more at www.scripps.edu.

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