Bioengineering Microphysiological Models of Sex-Specific Pathophysiology

Tulane University Of Louisiana, New Orleans LA

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Abstract

The interplay of biological sex and sex hormones has largely been ignored when developing human cell-based disease models. This lack of attention to the biological sex of cultured cells in cellular physiology research is due in part to an absence of literature defining sex-specific culture systems and methods. The long-term goal of this project in the Tulane COBRE for Sex-Based Precision Medicine is to develop human cell-based microphysiological systems (MPS) to serve as new approach methodologies for modeling the sex-specific pathophysiology of high-burden diseases. MPS models of human disease created with a sex-based approach will increase the relevance of mechanistic investigations, enhance the predictive accuracy of therapeutic screenings, and accelerate the development of more effective treatments. There are currently no reports that systematically compare the effects of sex hormones in cultured human cells of both sexes. Focusing on human cell-based models of the outer retinal microvasculature, we will first combine 2D and 3D culture assays to define the sex-specific effects of estrogen and androgen on bioenergetic capacity, vasculogenic capacity, and gene expression profiles. These analyses will determine optimal hormone concentrations for quantifying the response to proinflammatory or proangiogenic stimuli in female and male MPS models of microvascular physiology, including endothelial barrier function and sprouting angiogenesis. Inflammatory perturbation of endothelial barrier function and pathological neovascularization are core elements of microvascular pathologies such as diabetic retinopathy (DR). While there is no clearly established sexual dimorphism in DR incidence, known biological sex differences in the underlying mechanisms of inflammatory activation suggest the possibility of sex-specific pathophysiology and the potential to develop sex-based treatment approaches. We will use our validated MPS models of vascular permeability and angiogenesis in the outer retinal microvasculature as venues for exploring the broad hypothesis that estrogen and androgens modulate DR pathophysiology in a sex-specific manner. Phenotypic signatures occurring in response to sex hormone stimulation in 2D and 3D cell cultures will be referenced to infer potential mechanisms of action in the MPS assays. The functional consequence of sex hormone effects in female and male models will be verified using established pharmacological approaches to modulate hormone receptor signaling. Accrual of the datasets from these studies will help identify candidate biomarkers to inform further research on the development of sex-based precision treatments for DR. Collectively, this research will deliver adaptable sex-specific human cell culture systems and methods that can be adapted to develop more accurate new approach methodologies in preclinical science.