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Title page for ETD etd-03262018-230902


Type of Document Dissertation
Author Gnecco, Juan Sebastian
Author's Email Address juan.s.gnecco@vanderbilt.edu
URN etd-03262018-230902
Title Determining the Role of the Perivascular Microenvironment on Reproductive Function in an Organ-on-Chip Model of the Human Endometrium
Degree PhD
Department Pathology
Advisory Committee
Advisor Name Title
Pampee Young MD, PhD. Committee Chair
Andries Zijlstra, PhD Committee Member
David Aronoff, MD Committee Member
Kevin Osteen, PhD Committee Member
Lisa McCawley, PhD Committee Member
Keywords
  • vasculature
  • organ-on-chip
  • decidualization
  • Endometrium
  • microfluidic
Date of Defense 2018-03-16
Availability unrestricted
Abstract
The 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.
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