Spatial metabolomics and transcriptomics reveal cell type-specific dynamics in the placenta of patients with late-onset preeclampsia

Xiaowei Wei¹Qian Li¹Chuanmei Qin¹Weihong Zeng²Yuxu Liu²Jiawei Lu³Jiuming He⁴cailian chen⁵Xiaoqing Zhang⁵Yi Lin^1*

• ¹Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, 200233, Shanghai,, China
• ²Department of Obstetrics and Gynecology, Shanghai Jiao Tong University School of Medicine Affiliated International Peace Maternal and Child Health Hospital, Shanghai, China
• ³Shanghai Luming Biological Technology co. Ltd, 201102, Shanghai, China
• ⁴State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
• ⁵Department of Automation, Shanghai Jiao Tong University, Key Laboratory of System Control and Information Processing, Ministry of Education of China, 200240, Shanghai, China

Abstract Introduction: The placenta is vital for fetal development, but its growth can become disordered in pregnancy complications, particularly at the maternal–fetal interface. Preeclampsia, a severe condition that arises after the 20th week of pregnancy, is characterized by hypertension and other complications, posing significant risks to both mother and fetus. Despite its importance, the underlying mechanisms of preeclampsia remain poorly understood. Unraveling these mechanisms is essential for improving outcomes and advancing treatment strategies. Objectives: This study aimed to explore the spatial heterogeneity of the placenta and investigate the pathogenesis of late-onset preeclampsia (LOPE). Methods: We employed spatial transcriptomics (ST) and spatial metabolomics (SM) to map trophoblasts, fibroblasts, and immune cells, and analyze their transcriptomic and metabolomic profiles. A "spot-match" method was developed to integrate ST and SM data, revealing cell type-specific gene and metabolite changes during trophoblast differentiation. Results: The preeclamptic placenta showed increased fibroblasts and VCT proportions but a reduced SCT proportion. Complex interactions among trophoblasts, fibroblasts, and macrophages were observed in LOPE patients. Major metabolic reprogramming, particularly in glycerophospholipid and sphingolipid metabolism, was identified, potentially influencing trophoblast differentiation. Conclusion: Our ST and SM data offer new insights into LOPE mechanisms, providing valuable information for its prevention and treatment.