Microphysiologic Models of Human Ectocervical Tissue to Study Steroid Hormone Action During Homeostasis, Infection, and Oncogenic TransformationPublic Deposited
There is a shortage of research models that adequately represent the unique mucosal environment of human ectocervical tissue, which has limited the development of new therapies for treating infection or cancer. I hypothesized that engineering the microenvironment of ectocervical tissue with in vivo-like endocrine and paracrine support, would enable squamous differentiation and hormone response. An interdisciplinary approach was taken to generate and characterize three distinct microphysiologic tissue culture models to study hormone-action in the human cervix. These microphysiologic models mimicked many aspects of in vivo physiology, including squamous maturation, hormone response, and mucin production, which are important components of barrier defense. Additionally, mRNA transcripts for several mucins not previously reported in the ectocervix and the differentiation-dependent localization of known ectocervical mucins were identified in both native and engineered tissue. To investigate genomic pathways that may influence physiology and infectivity during the menstrual cycle, RNA sequence analysis was performed on patient-matched engineered tissue after follicular and luteal phase hormone treatments. Follicular phase hormones were associated with proliferation, transcription, and cell adhesion, while luteal phase samples expressed genes involved in immune cell recruitment, inflammation, and protein modifications. In summary, I developed three microphysiologic human ectocervical tissue models that differentiate, produce mucins, and respond to hormones, and defined ovarian hormone-action in the human ectocervix during the menstrual cycle, highlighting potential mechanisms that may influence infectivity. This will be useful for a variety of research applications, such as drug development and toxicology studies, development of preventative and therapeutic treatments, and basic research on hormone action in a critical reproductive tissue for women’s health that has been historically understudied.