Editorial: Physiology and pathophysiology of placenta

The modern understanding of the human placenta has evolved from viewing it as a simple transient barrier to recognizing it as a highly sophisticated, dynamic organ that dictates long-term health outcomes for both mother and child. Recent advances in placental biology are beginning to unravel the molecular and cellular mechanisms underlying these processes, revealing how disturbances in placental signaling, including hypoxia-and angiogenesis -related pathways, may contribute to a wide spectrum of pregnancy complications (1,2).At the core of placental development are trophoblast cells, whose migration and invasion are regulated by complex signaling cascades. Pathways such as Wnt, Notch, and TGF-beta are essential for branching morphogenesis (3), while dysregulation in these signals, including downstream inflammatory mediators and oxidative stress-related pathways, are linked to conditions like preeclampsia (PE) (4,5). Beyond native development, regenerative medicine is exploring the versatility of human amniotic membrane mesenchymal stem cells (hAmMSCs) (6). These cells exhibit the potential to differentiate into steroidogenic lineages when induced by factors like SF-1 and WT1, offering hope for treating endocrine disorders.One of the most revolutionary shifts in reproductive science is the discovery of the placental microbiota (7). Advances in high-throughput sequencing have challenged the "sterile womb" dogma, suggesting that low-level microbial communities, potentially originating from maternal oral or gut sites, play a role in local homeostasis. Imbalances in these communities are increasingly associated with preterm birth and fetal growth restriction (FGR). Complementing this environment are Hofbauer cells, the placenta's specialized macrophages, which act as primary immune responders to infections (ID: 1671127, not available DOI). Understanding their unique polarization and function is critical for decoding maternal-fetal immune dialogues.The placenta serves as a primary endocrine hub, secreting essential peptide hormones such as hCG and hPL that coordinate pregnancy (8). This hormonal activity is supported by sophisticated vesicular trafficking and secretion pathways within placental cells. Metabolic proteins also emerge as vital biomarkers of fetal well-being; for instance, the Klotho protein is significantly reduced in the placentas and blood of women with intrauterine growth restriction (IUGR) (9). This reduction likely influences fetal development through the GH/IGF-1 axis. Furthermore, in cases of gestational diabetes mellitus (GDM), circulating levels of GPIHBP1, a protein essential for triglyceride lipolysis, show significant correlations with neonatal birth weight and oxygenation, highlighting its role in maternal-fetal lipid metabolism (10).Clinical management of placental disorders remains a high-stakes endeavor. Placenta accreta spectrum represents a severe threat where abnormal placental invasion leads to life-threatening hemorrhages. Identifying risk factors for emergency cesarean sections, such as a history of previous cesareans and low preoperative hemoglobin, is crucial for improving outcomes (11). Additionally, decreased maternal plasma levels of APOA1 have been identified as a significant predictor of placenta accreta severity and the necessity for blood transfusions or hysterectomies (12).Maternal systemic conditions also leave a mark on the placenta; hypothyroidism during pregnancy is associated with distinct pathological features, including insufficient vascular perfusion and increased chronic inflammation (13). Rarer conditions, such as intraplacental choriocarcinoma, must be monitored through vigilant beta-hCG surveillance, as they can lead to spontaneous, massive fetomaternal hemorrhage with high perinatal mortality (14).The quest for protective agents has identified Pyrroloquinoline quinone (PQQ) as a promising nutrient. In experimental models, PQQ pre-conditioning has successfully alleviated inflammationinduced placental damage and improved fetal survival rates (15). Such protective systems are vital because placental health directly impacts the neonatal brain; dysregulation of the placental serotonergic system is now clearly linked to early impairments in infant neurodevelopmental scores (16).Finally, for the most vulnerable extremely preterm infants requiring extracorporeal life support, technology must account for neonatal biological specificities. Research has demonstrated that neonatal blood exhibits significantly higher susceptibility to hemolysis compared to adult human or standard porcine blood models (17). This finding necessitates the development of specialized miniaturized devices, such as artificial placentas, tailored specifically to the fragile nature of neonatal erythrocytes.Taken together, the studies included in this Research Topic underscore the remarkable complexity of the placenta as an endocrine, metabolic, immunological, and vascular organ that lies at the center of maternal-fetal health. By integrating insights from molecular biology, experimental models, clinical cohorts, and translational research, this collection highlights the multifaceted nature of placental function and its critical role in determining pregnancy outcomes and early life development. Continued interdisciplinary research in placental biology will be essential for improving the diagnosis, prevention, and treatment of pregnancy-related disorders and for advancing our understanding of how early life environments shape health across the lifespan.