LIV-AD-ON-CHIP · Unmasking insulin resistance triggering mechanisms using microphysiological two-organ systems as in vitro disease models of metabolic syndrome and non-alcoholic fatty liver disease

Unmasking insulin resistance triggering mechanisms using microphysiological two-organ systems as in vitro disease models of metabolic syndrome and non-alcoholic fatty liver disease

The proposed project represents an integrative and multidisciplinary endeavor aimed at developing and utilizing a microphysiological organ-on-a-chip model to create a human physiologically and physio-pathologically relevant in vitro insulin signaling model. Recognizing the persistent challenge of insulin resistance, despite decades of study using traditional clinical and cell culture approaches, the adoption of organ-on-a-chip technology promises novel insights into this field. While human organ-on-a-chip models have been established for drug screening using transformed cell lines, the limitations of such models underscore the necessity of employing more physiologically relevant human primary cells, particularly hepatocytes, over extended periods. To address this, the project outlines four specific objectives: 1. Establish methodologies for adipocyte and hepatocyte bioenergetic characterization on-chip (O1). 2. Differentiate stem cells into adipocyte-like and hepatocyte-like cells focusing on their bioenergetic competence (O2). 3. Develop a physiological model for liver-adipose tissue crosstalk (O3). 4. Utilize a physio-pathological model for insulin resistance studies (O4). Distinguishing itself from previous work, this project human primary mature adipocytes characterized for their bioenergetic metabolism. Additionally, innovative flexible multi-organ-interconnection concepts enable molecular studies of multi-organ diseases such as metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). These approaches pave the way for the introduction of other cell types, such as immune cells, facilitating a deeper understanding of disease mechanisms and enabling the creation of patient-specific disease models. The biomedical applications of this work are wide-ranging: (i) Biomarker discovery for early non-symptomatic manifestations of insulin resistance, potentially preventing the development of diseases like NAFLD and metabolic syndrome. (ii) Food science applications, including testing nutritional schemes using personalized long-term cultures. (iii) Identification of future pharmacologic targets to modulate or reverse the progression of insulin resistance at an early non-symptomatic state. In summary, this project offers a promising modular multi-organ platform for advancing our understanding of insulin resistance and related metabolic disorders, with implications for both basic research and practical applications in healthcare and nutrition.

Data: CORDIS, © European Union