Reduced SPARC in trophoblast promotes decidual M1 macrophage polarization and trophoblast dysfunction.

Abstract

Missed abortion (MA) is a complex pregnancy complication with multifactorial etiologies, including embryonic chromosomal anomalies and maternal endocrine disorders. Among these, immune dysregulation at the maternal-fetal interface has been recognized as a critical contributing factor. Secreted protein acidic and rich in cysteine (SPARC) is implicated in macrophage polarization and trophoblast function, but its role in MA-associated immune imbalance remains unclear. Decidual tissues were collected from 7 to 10 week MA patients and gestational age-matched healthy controls who underwent induced abortions. SPARC expression and macrophage phenotypes were assessed by Western blot and multiplex immunofluorescence staining for SPARC, CD68, CD86, and CD206. In vitro, THP-1 monocytes were differentiated into macrophages by PMA, which were then exposed to the conditioned media collected from SPARC-knockdown or control HTR8/SVneo trophoblasts. Cell viability, migration and apoptosis of HTR8/SVneo cells were evaluated under indirect co-culture with macrophages, with or without TNF-α neutralizing antibody. SPARC expression was significantly reduced in MA decidua, and its expression negatively correlated with the proportion of M1 macrophages, while positively correlated with M2 macrophages. SPARC knockdown in trophoblasts promoted macrophages M1 polarization, elevated TNF-α, and impaired macrophage-induced trophoblast viability, invasion, and survival. TNF-α neutralization partially rescued these effects. Mechanistically, SPARC promoted M2 polarization via the AKT/SP1 pathway, and its knockdown suppressed Akt phosphorylation and SP1 expression. Reduced SPARC in MA decidua drives M1 macrophage dominance and TNF-α-mediated trophoblast dysfunction through AKT/SP1 signaling, highlighting SPARC as a potential therapeutic target for MA.