Physiomimetic Models of Endometrioma Initiation

ABSTRACT Endometriosis is a multifactorial estrogen-dependent disease that affects 10% of all menstruating people. Endometriotic lesions occur throughout the peritoneal cavity and on the ovaries, leading to chronic pelvic pain and infertility. Clinical management focuses on surgical resection but improved care is severely limited by our poor understanding of processes driving lesion formation, persistence, and recurrence. While ovarian endometriosis lesions (endometriomas) are the most common, essential studies of lesion initiation and growth are largely intractable in vivo. There is a critical need for experimental tools to investigate processes that shape endometrioma lesion formation, treatment, and recurrence. The long-term goal of this research program is to develop a tissue engineering model of the endometrioma lesion microenvironment to study processes that shape shape lesion initiation, ovarian stroma invasion, and eventual persistence in a chronic inflammatory tissue microenvironment. Retrograde transport of endometrial tissue and menstrual effluent containing endometrial epithelial and stromal cells through the fallopian tubes into the peritoneal cavity is believed to contribute to lesion initiation. However, while the majority of menstruating people experience retrograde menstruation, only a subset develop endometriosis. Further, lesions are not ubiquitously spread through the peritoneal cavity and on the ovaries in each patient. Hence, while retrograde menstruation is likely necessary, it is not sufficient: lesion initiation must be triggered by more than just the presence of these cells. We focus on uncovering multicellular interactions that shape endometrioma lesion initiation and invasion that may explain the idiosyncratic nature of lesion distribution. We hypothesize tissue tropism associated with the ovarian microenvironment provides cues that influence the activity of multicellular cohorts of endometriotic epithelial and stromal cells responsible for lesion initiation. And subsequently, angiocrine signals from the underlying ovarian perivascular environment accelerate lesion invasion. The objective of this project it to demonstrate a physiomimetic model of the endometrioma lesion microenvironment, combining 2D and 3D biomaterials tools with human menstrual effluent specimens to investigate processes responsible for lesion initiation and invasion. To accomplish this goal, we will first identify cues that inform adhesion of endometriotic epithelial and stromal cell cohorts responsible for lesion initiation (Aim 1). Then we will define patterns of endometrioma invasion in response to the ovarian microvascular environment (Aim 2). We will generate unprecedented data regarding variation of lesion initiation and invasion not possible in vivo. Understanding how tissue tropism and ovarian vascular signals shape patterns of lesion initiation and invasion is essential for the design of effective and equitable therapeutic strategies. Tissue engineering models benchmarked here will also provide an essential foundation for future study of the influence of chronic inflammatory signals on lesion persistence and recurrence.