The impact of cannabigerol exposure on human endometrial stromal cells decidualization

Decidualization denotes the inflammatory reprogramming of endometrial stromal cells (EnSC) into progesterone-dependent decidual cells (DC), a process essential for embryo implantation and placenta formation. Decidualization also gives rise to progesterone-resistant decidual-like senescent cells (dSC), involved in extracellular matrix (ECM) remodelling and menstruation. Cannabigerol (CBG) is a non-psychotropic phytocannabinoid present in cannabis-derived products, whose impact on endometrial function remains poorly understood. The effects of CBG on decidualization were studied using an immortalized human endometrial stromal cell line (St-T1b) and primary EnSC. Cell viability was assessed following exposure to CBG (1-10 µM) during decidualization induction. CBG (2 µM) was used to evaluate its impact on decidual marker genes expression, IL-6 secretion, and transcriptomic changes (RNA-Seq). CBG inhibited the induction of the canonical decidual marker genes PRL and IGFBP1 in differentiating St-T1b cells, while this repression was not observed in decidualizing primary EnSC. Also, in these cells, CBG did not affect progesterone-dependent regulation of SCARA5 or DIO2, nor the expression of IL1RL1 and CLU, marker genes of anti-inflammatory DC and pro-inflammatory dSC, respectively. However, IL-6 secretion was reduced during the initial pro-inflammatory phase of decidualization, suggesting alterations in the cellular reprogramming of EnSC. RNA-Seq analysis identified 34 differentially expressed genes mostly associated with mitochondrial activity, lipid biosynthesis, inflammatory response and ECM remodelling. Although CBG did not disrupt canonical decidual markers in primary cells, the modulation of DC metabolism, ECM remodelling, and inflammatory response may constitute a significant risk factor for adverse pregnancy outcome.