Development of a pancreas-liver organ-on-chip coculture model for organ-to-organ interaction studies

Abstract

Type 2 diabetes mellitus (T2DM) is a widespread chronic disease with a high prevalence of comorbidity and mortality. The exponential increase of TD2M represents an important public health challenge and leads a strong demand for the development of relevant in vitro models to improve mechanistic understanding of diabetes and identify new anti-diabetic drugs and therapies. These models involve considering the multi-organ characteristic of T2DM. The organ-on-chip technology has made it possible to connect several organs thanks to dedicated microbioreactors interconnected by microfluidic network. Here, we developed pancreas-liver coculture model in a microfluidic biochip, using rat islets of Langerhans and hepatocytes. The behavior and functionality of the model were compared to islets and hepatocytes (with/without insulin) monocultures. Compared to monoculture, the islets coculture presented high C-peptide and insulin secretions, and downregulation of Pdx1, Glut2, App, Ins1, Neurod, Neurog3 and Gcgr genes. In the hepatic compartment, the monocultures without insulin were negative to CK18 staining and displayed a weaker albumin production, compared to monoculture with insulin. The hepatocytes cocultures were highly positive to INSR, GLUT2, CK18 and CYP3A2 immunostaining and allowed to recover mRNA levels similar to monocultures with insulin. The result showed that islets could produce insulin to supplement the culture medium and recover hepatic functionality. This model illustrated the potential of organ-on-chip technology for reproducing crosstalk between liver and pancreas.