We have successfully identified a disease-associated subset of CD24+ decidual stromal cells that could potentially contribute to the development of RM through the impairment of decidual immune tolerance. Targeting these specific CD24+ DSCs might hold promising prospects for therapeutic interventions in the clinical management of RM.

To explore the heterogeneity of CD24+ decidual stromal cells (DSCs) in patients with recurrent miscarriages (RMs). Design: We have discerned that the expression of CD24 serves to differentiate two stable and functionally distinct lineages of DSCs. The heterogeneity of CD24+ DSCs has been scrutinized, encompassing variances in stromal markers, transcriptional profiles, metabolic activity, and immune regulation. Setting: Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University; Shanghai Institute of Immunity and Infection, Chinese Academy of Science. Patients: A total of 129 early decidual samples were obtained, comprising 36 from healthy donors and 93 from patients with RMs. Blood samples were collected before the surgical procedure. Paraffin-embedded segments from 20 decidual samples of patients with RMs were obtained. Interventions: None. Main outcome measures: The flow cytometry was used to quantify the expression of CD24+ DSCs in both healthy donors and patients with RMs, although it also evaluated the cellular heterogeneity. To ascertain the transcriptomic profiles of CD24+ DSCs by reanalyzing our single-cell transcriptomic data. Additionally, to measure the metabolomic activity of CD24+ DSCs from patients with RMs, ultraperformance liquid chromatography-mass spectrometry was employed. Through the implementation of a coculture system, we unraveled the role of CD24+ DSCs in immune regulation.

Patients with RMs exhibit a notable enrichment of CD24+ DSCs, revealing a pronounced heterogeneity characterized by variations in stromal markers and transcriptional profiles. The heightened enrichment of CD24+ DSCs may play a pivotal role in triggering decidual inflammation and dysfunction in decidualization. Furthermore, CD24+ DSCs showed diverse metabolic activities and impeded the induction of naïve CD4+ T cells into regulatory T cells through the abundant secretion of 3-hydroxyisovaleric acid. Finally, our investigations have revealed that intraperitoneal administration of 3-hydroxyisovaleric acid in mouse models can elevate the risk of RM.