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Juan Gnecco, Ph.D.

Department: Pathology, Microbiology & Immunology, 2018

Faculty Mentor: Kevin Osteen, Ph.D.

Dissertation Title: Determining the Role of the Perivascular Microenvironment on Reproductive Function in an Organ-on-Chip Model of the Human Endometrium

Dissertation AbstractThe endometrium is the tissue lining the inner cavity of the uterus in which nidation and pregnancy maintenance occurs. To date, there are no physiological models that recapitulate the human endometrial microenvironment; thus, our understanding of the role of the vasculature in regulating endometrial reproductive processes remains largely unknown. “Organs-on-a-Chip” (OoC) models are compartmentalized microfluidic cultures of heterotypic cells that better approximate the human in vivo conditions. Herein, we engineered and established an OoC model of the human endometrial perivascular stroma to test the hypothesis that the endometrial vascular endothelium plays a role in regulating both normal reproduction function and disease pathogenesis. We examined the crosstalk between prolonged cultures of human endometrial endothelial cells and stromal fibroblasts under hormonal and physiological signals. Our studies demonstrated that shear stress-induced secretion of specific endothelial cell-derived prostaglandins enhances perivascular response to progesterone via a paracrine mechanism. Altogether, these translational findings show that the endometrial vascular endothelium plays a key physiologic role during the initiation of perivascular decidualization in the human endometrium. Furthermore, vascular dysfunction alters the immune-endocrine inflammatory axis of the endometrium and contributes to the pathogenesis of endometrial disorders. Specifically, endocrine disruptors such as the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) promoted an enhanced immune cell recruitment. Identification of specific inflammatory mediators necessary during endometrial reproductive processes may have clinical utility as therapeutic targets for reproductive disorders such as infertility, endometriosis, preeclampsia and poor pregnancy outcomes.