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Yang-Xue-An-Tai Decoction Treats URSA by regulating the differentiation of proliferating decidual stromal cells
Guanshan Li1, Linlan Hu2, Jiaxin Tang2
1Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing Maternal and Child Health Care Hospital, Beijing, 100026, China.
Ethnopharmacological Relevance:
Unexplained recurrent spontaneous abortion (URSA) accounts for approximately 50% of all recurrent spontaneous abortion cases, severely endangering the physical and mental health of women of childbearing age. Yang-Xue-An-Tai Decoction (YXAT), a traditional Chinese medicine (TCM) in-hospital preparation, has been clinically effective and safe for URSA treatment for over 30 years, but its underlying mechanism remains unclear.
Aim Of The Study:
The purpose of this study was to explore the pharmacological mechanism of YXAT in the treatment of URSA, focusing on clarifying its multi-target mechanism in regulating the differentiation of decidual stromal cell (DSC) subtypes.
Materials And Methods:
The classic Clark mouse model of URSA was established to verify YXAT's improvement effect on abortion. Single-cell RNA sequencing (scRNA-seq) was employed to construct the uterine single-cell atlas of model and YXAT-treated mice at gestational day 7.5 (GD7.5). YXAT's regulation on decidualization was verified by detecting decidualization markers; decidual stromal cell subtypes were analyzed, and its regulatory effect on subtype differentiation was confirmed via pseudotime analysis and intercellular communication. Moreover, YXAT's role in regulating abnormal decidual stromal cell differentiation in URSA was validated in animal and clinical samples.
Results:
YXAT significantly improved decidualization and improved pregnancy outcomes in URSA mice. Subcluster analysis of DSCs revealed that proliferating DSCs (proDSCs)-a central hub for DSC differentiation-were abnormally downregulated in URSA mice, and this reduction was restored by YXAT, with a significantly better effect than that of the positive drug dydrogesterone. Integrated analysis identified Lgals1 as a key overlapping gene regulated by YXAT and linked to proDSC differentiation. We propose that Lgals1 acts as a candidate regulator, and the recovery of Lgals1 expression coincides with the restoration of proDSC differentiation following YXAT treatment. Additionally, URSA mice exhibited enhanced NK cell-proDSC communication with excessive inflammatory activation (e.g., Spp1-Cd44, Gzma-Pard3) and immune suppression-related ligand-receptor pairs (e.g., Spp1-(Itgav + Itgb5), Lamb2-Dag1), which were attenuated by YXAT. The abnormal downregulation of proDSCs was further verified in human URSA samples, highlighting its clinical relevance.
Conclusions:
Disordered proDSC differentiation correlates with defective decidualization and adverse pregnancy phenotypes in URSA mice. Multiple favorable cellular and molecular changes are observed alongside YXAT intervention, including recovered proDSC abundance, restored expression of the differentiation-associated gene Lgals1, and normalized abnormal NK cell-proDSC intercellular signaling. These correlative observations offer new insights into the clinical potential of YXAT and advance our understanding of TCM interventions against URSA.