Celiac disease-on-chip: Modeling a multifactorial disease in vitro.

Renée Moerkens,Joram Mooiweer,Cisca Wijmenga,Sebo Withoff

doi:10.1177/2050640619836057

Abstract

Conventional model systems cannot fully recapitulate the multifactorial character of complex diseases like celiac disease (CeD), a common chronic intestinal disorder in which many different genetic risk factors interact with environmental factors such as dietary gluten. However, by combining recently developed human induced pluripotent stem cell (hiPSC) technology and organ-on-chip technology, in vitro intestine-on-chip systems can now be developed that integrate the genetic background of complex diseases, the different interacting cell types involved in disease pathology, and the modulating environmental factors such as gluten and the gut microbiome. The hiPSCs that are the basis of these systems can be generated from both diseased and healthy individuals, which means they can be stratified based on their load of genetic risk factors. A CeD-on-chip model system has great potential to improve our understanding of disease etiology and accelerate the development of novel treatments and preventive therapies in CeD and other complex diseases.

Highlights

0.6% to 1%1 of the Caucasian population has celiac disease (CeD), a complex immunemediated disease characterized by a strong inflammatory reaction to dietary gluten in genetically predisposed individuals
CeD is primarily characterized by damage to the small intestine, patients can suffer from extraintestinal manifestations such as anemia, osteoporosis and ataxia.[5,6]
Using human induced pluripotent stem cell (hiPSC) as a starting point, the effect of a diseaseassociated genotype can be evaluated in multiple diseaserelevant cell types, either individually or in combination, in an intestine-on-chip

Summary

Introduction

0.6% to 1%1 of the Caucasian population has celiac disease (CeD), a complex immunemediated disease characterized by a strong inflammatory reaction to dietary gluten in genetically predisposed individuals. The system provides mechanical forces to simulate the physical microenvironment of the intestine through fluid flow that introduces shear stress on the cells and two vacuum compartments on the sides that create a peristalsislike motion These mechanical forces induce epithelial cells to spontaneously form polarized 3D villus-like structures that contain cells expressing markers characteristic of differentiated IECs (i.e. adsorptive enterocytes, mucus-producing goblet, Paneth and enteroendocrine cells).[39,57,58,59] The resulting epithelial layer exhibits basic functional properties, such as mucus production, high barrier resistance, activity of brush border and drug-metabolizing enzymes, and high efficiency in nutrient uptake because of the increased intestinal surface. Using hiPSCs as a starting point, the effect of a diseaseassociated genotype can be evaluated in multiple diseaserelevant cell types, either individually or in combination, in an intestine-on-chip This model is unique because it integrates (1) the CeD-associated genetic background, (2) the interaction between disease-relevant cell types, (3) any relevant environmental stimuli and (4) the physical microenvironment of the intestine in a complex yet controllable manner. To be used for drug screening and/or addressing pharmacogenetic questions, high-

Effect of CeD -associated cytokines

Findings

Conclusion