Endometrial stromal cell senescence: A non-negligible factor in recurrent pregnancy loss

According to guidelines from the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM), recurrent pregnancy loss (RPL) is defined as two or more clinically confirmed pregnancy losses (documented by ultrasound or histopathology). It has an incidence of approximately 1–2%. About 15% of clinically recognized pregnancies end in miscarriage, and 50–60% of sporadic cases are attributable to chromosomal abnormalities in the embryo. However, the proportion of embryonic chromosomal abnormalities is relatively low in RPL. And with each additional miscarriage, the incidence of normal chromosomal miscarriage increases, while the probability of a successful pregnancy decreases. This phenomenon indicates that, in addition to embryonic factors, maternal uterine determinants contribute substantially to elevated miscarriage rates. With the delay of childbearing age, women’s risks of miscarriage and other reproductive disorders rise markedly after the age of 30, and features of reproductive aging often precede chronological age. Although research on reproductive aging has historically centered on the ovary, accumulating evidence now underscores that the endometrium also plays a critical role in determining pregnancy outcomes.

Despite advances, effective interventions for RPL remain scarce, and in a substantial proportion of patients, the underlying cause is still unclear. Whereas earlier work focused largely on embryonic quality and endocrine or immunologic anomalies, increasing evidence highlights the central role of the endometrial environment in supporting embryo implantation and sustaining pregnancy. Among determinants of implantation, the functional state of EnSCs is particularly critical. Stromal-cell aging has been posited as an important pathological mechanism in RPL and has gained wide attention in basic research and clinical practice. EnSCs are key endometrial constituents and the principal mediators of decidualization. During the luteal phase, hormonal signals drive EnSCs to differentiate into decidual stromal cells, establishing a supportive micro-environment for embryo implantation and placental development. Conversely, premature senescence of EnSCs, or the aberrant accumulation of senescent cells, disrupts decidualization, diminishes endometrial receptivity, and compromises the maternal–fetal interface, thereby increasing the risk of preterm birth, fetal growth restriction, preeclampsia, and miscarriage. Abnormal EnSCs senescence has been documented in the decidua of women with recurrent miscarriage, implicating it in the pathogenesis of RPL.

This review aims to provide a systematic account of EnSCs' senescence in physiological and pathological pregnancy, delineate its putative mechanistic contributions to RPL, and evaluate emerging interventions targeting EnSCs' senescence, thereby providing a possible new theoretical basis and research direction for the treatment of RPL in the future.