(H-313) Human Multiorgan Microphysiological System for the Study of Interorgan Crosstalk in Systemic Metabolism

Introduction: Normal glucose homeostasis is a fundamental necessity for survival, resulting from complex crosstalk between different organs. Diabetes, obesity, cardiovascular diseases, and accelerated aging are the cohort of illnesses constituting the metabolic syndrome caused by abnormal glucose metabolism. Despite much progress, this group of illnesses represents some of the most significant health issues of our time. Thus, new tools relevant to human biology are needed to understand the mechanisms that govern dietary metabolism and how their disbalance leads to pathology. Recently, microphysiological systems (MPSs) have emerged as a complementary approach that supports the reconstruction of complex human biology, the cell's natural 3D architecture and cellular heterogeneity, and the fluidic communication between multiple human tissue models.

Materials & Methods: Here, we report a new portable five-organ micro physiology system to study the crosstalk between the human gut, liver, pancreas, skeletal muscle, and adipocytes under metabolically defined conditions. The device consists of a battery-powered peristaltic pump and a Bluetooth-controlled motherboard that allows for various perfusion rates to be adjusted from the bench. The main chamber consists of five wells designed to hold a variety of membrane inserts.  Each well connects with a common culture medium through a simple perfusion system with a flow rate of up to 20ml/min. Further, we have implemented a real-time glucose and lactate monitor within the perfusion lines for consistent evaluation of glucose turnover.  All tissues are first matured separately in their respective media, and once physiological benchmarks are reached, interaction studies commence. Here we report new insights into the crosstalk between the five tissues under fed or fasted states. We have evaluated the system against three classes of the most-often prescribed drugs Metformin, statins, and GLP-1 agonists. 

Results: Here, we report that a four-day interaction leads to significantly different tissue responses compared to these in isolation. Proteomic, metabolic, and transcriptomic changes mirror known physiological responses to low or high glucose conditions and reveal new signaling cascades in each tissue type. While insulin secretion by pancreatic islets is considerably increased, as measured by C-peptide, the actual levels of insulin are lowest in high glucose challenges, which is explained by the high insulin intake of interacting tissues. We show that Metformin and Semaglutide successfully regulate glucose levels in the interacting system.  These results correlate with clinical observation and support the efficiency of our system in mimicking systemic glucose metabolism.

Discussion & Conclusion: The five-organ platform presented here offers a new opportunity to dissect interorgan crosstalk in relation to human metabolism systematically. The autonomous system with real-time glucose sensing, paired with remote control, simplifies translating such systems into various laboratory settings. This ease is further increased by the ability of the system to house commercially available membrane inserts.

The main chamber can be sterilized and cleaned, reducing the waste generated in biomedical research.  Multiorgan microphysiological systems are valuable tools in our exploration of human physiology and mark an important stepping-stone in the search for new therapies against metabolic diseases.