Distinct decidualization and senomorphic responses in endometrial vs. menstrual blood stem/stromal cells: implications for reproductive therapies

BACKGROUND: Decidualization, the process of endometrial stem/stromal cell (EnSCs) differentiation, is essential for embryo implantation and pregnancy maintenance. Menstrual blood-derived stem/stromal cells (MenSCs), although often considered as surrogates of EnSCs, represent a distinct population. Pharmacologic modulation of cellular senescence using senomorphics has emerged as a promising strategy in reproductive medicine. This study investigates the decidualization capacity of EnSCs and MenSCs and evaluates how senomorphic agents influence their senescence, metabolic profile, and inflammatory response. METHODS: Primary EnSCs and MenSCs were isolated, characterized, and subjected to in vitro decidualization using standardized protocols. Cells were classified as well-decidualized (WD) or poorly-decidualized (PD) based on the extent of decidualization. Six senomorphic compounds were applied before and during decidualization. Senescence-associated β-galactosidase activity, IL-6 secretion, glycolytic intermediates, and global metabolomic changes were assessed before and after treatment with senomorphics. RESULTS: MenSCs exhibited accelerated but limited and prolonged decidualization capacity compared to EnSCs. Metabolic reprogramming in EnSCs at day 6 resembled that of MenSCs at day 3. Decidualization induced differential changes in glycolysis-related metabolites, senescence markers, and IL-6, especially in PD cells. Treatment with six senomorphics modulated these effects in a context-dependent manner. Exposure during decidualization increased senescence in both WD and PD sources, whereas pretreatment increased senescence in WD EnSCs but decreased it in PD EnSCs. Notably, senomorphics shifted the metabolomic profile of PD EnSCs toward a WD-like state. CONCLUSIONS: EnSCs and MenSCs differ in decidualization dynamics, metabolism, and response to senomorphic modulation. Senomorphics may be strategically employed to reduce senescence in patients with impaired endometrial decidualization, offering therapeutic potential in reproductive pharmacology.