National Centers for Translational Research in Reproduction and Infertility

Development of Human Endometrium for Embryonic Implantation

University of California, San Francisco

PI:  L. Giudice

Cyclic tissue regeneration and receptivity to embryonic implantation are key functions of human endometrium. Recently, endometrial mesenchymal stem/progenitor cells have been identified, which are the likely precursor of the endometrial stromal fibroblast. Progesterone differentiation of the latter is essential to establish and maintain pregnancy, and this process is abnormal in endometriosis, a disorder characterized by infertility and poor pregnancy outcomes. Molecular mechanisms that underlie this abnormal P4 response are not well understood, although recent evidence from our lab and others suggests an epigenetic contribution. Whether P4-resistance is inherited from the mesenchymal stem cell or is acquired de novo by the stromal fibroblast through epigenetic mechanisms is not known. The central hypothesis of this project is that endometrial mesenchymal stem cell differentiation and endometrial stromal fibroblast P4 responsiveness involve hormone-dependent/independent pathways and epigenomic transitions that are altered in endometriosis, affecting the functions of these cells in tissue regeneration, fertility, and pregnancy outcome. Enforcing these considerations are recent new evidence from our lab and others of epigenetic alterations linked directly to endometriosis, involvement of the epigenome in endometrial steroid hormone responsiveness and abnormalities in endometriosis, and that endometrial mesenchymal stem cell gene expression and functionality differ in women with and without disease. We propose 3 specific aims that test the following hypotheses: Aim 1. endometrial mesenchymal stem cell lineage differentiation, driven by specific signaling pathways, gives rise to endometrial stromal fibroblast progeny with P4 resistance in endometriosis. Aim 2. abnormalities in DNA methylation in endometrial stromal fibroblasts contribute to the P4-resistance observed in women with endometriosis and are inherited from their progenitor, the endometrial mesenchymal stem cell. Aim 3: abrogated decidualization of human endometrial stromal fibroblasts in endometriosis affects trophoblast function, characteristic of pregnancy complications observed in women with endometriosis. The expected outcomes are an in-depth understanding of the roles of endometrial mesenchymal stem cells and stromal fibroblasts in endometrial maturation, early pregnancy, and abnormalities in endometriosis that will direct clinical translation to prevent or treat endometriosis-related infertility and optimize pregnancy outcomes. We shall interact extensively with Project I in cell signaling pathways and networks, Projects II and III on trophoblast function, the pilot project on endometriosis pathogenesis, Core B for extensive bioinformatics analysis, and Core C for education outreach.