Proteomic Study of Fetal Membrane: Inflammation-Triggered Proteolysis of Extracellular Matrix May Present a Pathogenic Pathway for Spontaneous Preterm Birth

Abstract

Introduction: Spontaneous preterm birth (sPTB), which predominantly presents as spontaneous preterm labor (sPTL) or prelabor premature rupture of membranes (PPROM), is a syndrome that accounts for 5-10% of live births annually. The longterm morbidity in surviving preterm infants is significantly higher than that in full-term neonates. The causes of sPTB are complex and not fully understood. Human placenta, the maternal and fetal interface, is an environmental core of fetal intrauterine life, mediates fetal oxygen exchange, nutrient uptake, and waste elimination and functions as an immune-defense organ. In this study, the molecular signature of preterm birth placenta was assessed and compared to full-term placenta by proteomic profiling. Materials and Methods: Four groups of fetal membranes (the amniochorionic membranes), with five cases in each group in the discovery study and 30 cases in each group for validation, were included: groups A: sPTL; B: PPROM; C: full-term birth (FTB); and D: full-term premature rupture of membrane (PROM). Fetal membranes were dissected and used for proteome quantification study. Maxquant and Perseus were used for protein quantitation and statistical analysis. Both fetal membranes and placental villi samples were used to validate proteomic discovery. Results: Proteomics analysis of fetal membranes identified 2,800 proteins across four groups. Sixty-two proteins show statistical differences between the preterm and fullterm groups. Among these differentially expressed proteins are (1) proteins involved in inflammation (HPGD), T cell activation (PTPRC), macrophage activation (CAPG, CD14, and CD163), (2) cell adhesion (ICAM and ITGAM), (3) proteolysis (CTSG, ELANE, and MMP9), (4) antioxidant (MPO), (5) extracellular matrix (ECM) proteins (APMAP, COL4A1, LAMA2, LMNB1, LMNB2, FBLN2, and CSRP1) and (6) metabolism of glycolysis (PKM and ADPGK), fatty acid synthesis (ACOX1 and ACSL3), and energy biosynthesis (ATP6AP1 and CYBB).

IL-27 Mediates Th1 Cells Infiltration in Fetal Membranes in Preterm Labor

“…This was in consistent with a previous study that mRNA levels of CXCL9, CXCL10, and CXCL11 in the FMs of patients with chronic chorioamnionitis were higher than the control group [51]. And ICAM-1 was over-expressed in FMs from women with PL than TL by proteomic analysis [52]. Besides, it was identified that these chemokines released from FMs could recruit immune cells [31].…”

High-Throughput Sequencing to Investigate lncRNA-circRNA-miRNA-mRNA Networks Underlying the Effects of Beta-Amyloid Peptide and Senescence on Astrocytes

“…HSPH1 has been found to be associated with proteolysis in differentiated neurons ( Deane and Brown, 2017 ). EPHB2 ( Ibrahim et al, 2018 ; Pan et al, 2020 ) TNF-α/nuclear factor-kappa B signaling has been reported to worsen cognitive impairment ( Tang et al, 2019 ). PDGFA is important for the growth and maintenance of the nervous system ( Cardona et al, 2021 ).…”

Preterm Labor, a Syndrome Attributed to the Combination of External and Internal Factors

“…A proteomic study of fetal membrane between preterm and full-TL revealed 62 proteins differentially expressed, which were involved in inflammation, T cell/macrophage activation, metabolism and synthesis, cell adhesion, proteolysis, and extracellular matrix pathways. 84 As an important barrier between fetus and mother, cortisol degradation and regeneration in the fetal membranes is a requisite event in parturition. 90 Cortisol involves in the rupture of fetal membranes through decreasing collagen I, III, IV, or inducing serum amyloid A1 to remodel extracellular matrix.…”

“…83 Placenta RNA-seq and metabolomics studies suggest that placenta mitochondrial function and energy metabolism are altered, and the imbalanced glycolysis and unconventional lactate oxidation may be associated with sPTL. 84,85 The placenta-derived extracellular vesicles proteins proteome revealed that nonspecific inflammation coagulation was upregulated while complement activation-related proteins were downregulated in cargo from first trimester in sPTL. 86 These differentially expressed molecules in placenta exerted different roles in the occurrence of sPTL.…”