Endometriosis-derived iPSCs reveal conserved stromal maturation and endocrine responsiveness

Abstract

Endometriosis is a chronic, hormone-dependent disease characterized by altered endometrial stromal function, but mechanistic and translational studies have been hindered by the lack of tractable human models. Here, we establish an induced pluripotent stem cell (iPSC)–based platform derived from patients with endometriosis to model endometrial stromal differentiation in a controlled human context. Using a defined differentiation protocol, endometriosis-derived iPSCs transition from pluripotency through mesenchymal commitment toward stromal-like states and acquire transcriptional hormone responsiveness. Transcriptomic analyses reveal coordinated repression of pluripotency and proliferative programs with induction of stromal lineage signatures. Comparison with independent transcriptomic datasets demonstrated that in vitro–derived stromal cells progressively acquired gene expression profiles resembling eutopic endometrial stromal programs in endometriosis. Conditioned media from iPSC-derived stromal cells also induced transcriptional reprogramming in THP-1 macrophage-like cells. Together, these findings establish a patient-derived platform for investigating stromal differentiation and stromal-immune interactions in endometriosis.