AI Insight
This study identifies growth differentiation factor 15 (GDF15) produced by the placenta as a critical regulator of fetal growth. Using mouse and pig models, researchers found that placental GDF15 enters fetal circulation and activates the STAT3 signaling pathway in the fetal liver, which in turn stimulates production of IGF2, a key growth factor. When placental GDF15 is deficient, fetuses develop growth restriction, but targeted delivery of GDF15 using lipid nanoparticles to the placenta successfully reverses this condition.
Why it matters
This research reveals a previously unknown placenta-to-fetal-liver communication pathway that could lead to new treatments for fetal growth restriction, a serious pregnancy complication affecting 5-10% of pregnancies worldwide. The demonstrated effectiveness of targeted GDF15 delivery using nanoparticles suggests a potential therapeutic approach that could reduce perinatal morbidity and mortality.
Understand the Science
by Xiao Peng Liu, Xiao Zhang, Chun Xia Cai, Miao Miao Qin, Xiang Kai Leng, Jia Hao Chen, Yi Fan Han, Jun Ying Xiao, Jia He Huang, Jiang Wei Wu
Fetal growth restriction (FGR) is a major cause of perinatal morbidity and mortality, yet its underlying mechanism remains elusive. Here, we show that growth differentiation factor 15 (GDF15) levels are significantly reduced in the placenta and fetal circulation in mouse and pig FGR models and correlate positively with fetal weight. Placenta-specific GDF15 deficiency causes FGR, while placenta-specific Gdf15 mRNA delivery through targeted lipid nanoparticle (LNP) effectively alleviates FGR. Mechanistically, placental GDF15 is a major contributor to the fetal circulating GDF15 pool and enters the fetal compartment, where it activates the hepatic STAT3 signaling pathway to stimulate IGF2 production during pregnancy. Placental GDF15 deficiency decreases hepatic STAT3 phosphorylation and IGF2 levels in fetuses. Inhibition of STAT3 in primary mouse fetal hepatocytes blocks GDF15-induced IGF2 upregulation. Placenta-specific Gdf15 mRNA-LNP administration rescues the decreased hepatic p-STAT3 and IGF2 levels in FGR fetuses. Collectively, our findings identify a placenta-fetal liver metabolic axis where placental GDF15 promotes fetal growth by activating the fetal hepatic STAT3-IGF2 pathway, revealing a potential therapeutic target for FGR.