Study Identifies FSP1+ Stromal Cell Crosstalk and Cellular Senescence as Drivers of Decidualization Defects in Adenomyosis

A study published in Human Reproduction demonstrates that FSP1+ stromal cells drive GAS6-MERTK-mediated macrophage efferocytosis and subsequent TNF-α-induced stromal cell senescence, identifying a potential target pathway for treating decidualization impairment in adenomyosis.

Researchers from Nanjing Drum Tower Hospital analyzed mid-secretory phase eutopic endometrial samples from patients with adenomyosis using single-cell RNA sequencing (scRNA-seq).

The study authors reported a significant elevation of Fibroblast-Specific Protein 1 (FSP1)+ stromal cells within the endometrium of these patients during the mid-secretory phase.

The authors reported that these FSP1+ stromal cells orchestrate the secretion of GAS6 via the transcription factor ZBTB7A, which interacts with MERTK receptors on macrophages to facilitate efferocytosis.

The activated macrophages subsequently secrete TNF-α, which was shown to induce cellular senescence in adjacent endometrial stromal cells, leading to compromised decidualization marked by reduced PRL and IGFBP1 levels.

Adenomyosis is a major cause of endometrial receptivity failure, implantation failure, and pregnancy loss, but the cellular mechanisms have remained poorly defined.

This research establishes a direct link between immune cell activity (efferocytosis) and localized somatic cellular senescence in reproductive tissue pathology.

Targeting the GAS6-MERTK-TNF-α pathway, or clearing the resulting senescent stromal cells, presents a potential therapeutic strategy for addressing impaired decidualization and improving fertility outcomes.

The discovery that localized cellular senescence drives reproductive tissue failure suggests a broader therapeutic scope for companies developing senolytics beyond systemic age-related diseases.

Therapies focused on immune-mediated senescent cell clearance or target pathways regulating cellular senescence could potentially find applications in female reproductive health and fertility preservation, provided these mechanisms are validated in larger clinical cohorts.

Further preclinical evaluation of MERTK inhibitors and senolytic agents in human endometrial assembloids and knockout mouse models to confirm if halting stromal cell senescence can restore decidualization.