CAREER: Engineering sex-based human cell culture methods and microphysiological systems

About This Grant

Biological sex influences normal physiology and the manifestation of disease. Severe illnesses such as cardiovascular diseases and cancers can exhibit profound sex differences in their occurrence, progression, and response to treatment. Historically, the research models used in preclinical science to develop new drugs do not sufficiently account for sex differences. For example, lab experiments testing new drug compounds typically do not examine effects in both female (XX sex chromosomes) and male (XY sex chromosomes) cells. This is due in part to the absence of distinct methods for culturing female and male cells with the right combination of sex hormones such as estrogen and testosterone. This CAREER project will explore research and development of sex-based human cell culture methods and engineered tissue models. The research will be integrated with university education and K-12 outreach that emphasizes the roles of individual biological differences such as age, sex and genetic background in health and disease, thereby helping students connect with medical science research. Principles of sex-based biology and medicine will be integrated in undergraduate and graduate physiology curricula in biomedical engineering. Completion of the proposed research will deliver female and male culture medium formulations with defined sex hormone compositions and engineered tissue models for studying sex differences in the retina, skin, and other organs. Collectively, these broadly adoptable innovations may facilitate the development of sex-based medicines that can improve clinical outcomes. Completion of the proposed CAREER activities will deliver validated sex-specific human cell culture methods and microphysiological models of the microvasculature that serve as venues for investigating: (i) sex-specific cellular physiology, (ii) sexual dimorphisms in disease, and (iii) sex-specific pharmacology. Female (XX) and male (XY) media formulations with defined sex hormone compositions (mixtures of estradiol, dihydrotestosterone, and progesterone) will be validated by benchmarking transcriptomic profiles against published datasets from biopsied endothelial cells of both sexes (XX and XY). Focusing on effects in endothelial cells of multiple sources will elucidate the interplay between sex hormone effects and tissue-specific phenotypes. Benchmarked sex-specific states in culture will be correlated with functional outputs in microphysiological systems assays of angiogenesis and vascular permeability, processes that are central to homeostasis and pathophysiology of most organs. These systems and methods will be applied to define sex differences in VEGF-mediated endothelial activation and inhibition by glucocorticoids, as paradigms of physiological regulation and pharmacologic response, respectively. The foundational scientific knowledge and new methodologies for sex-based culture methods resulting from this research can increase the clinical impact of human cell-based models of numerous diseases. This project is jointly funded by the Engineering of Biomedical Systems (EBMS) Program and the Established Program to Stimulate Competitive Research (EPSCoR). This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.