Potential Use of Human Stem Cell-Derived Intestinal Organoids to Study Inflammatory Bowel Diseases

Abstract

Inflammatory bowel disease (IBD) is a chronic remitting disorder with increasing incidence worldwide. The intestinal epithelial barrier plays a major role in IBD, contributing to its pathogenesis, evolution, and perpetuation over time. Until recently, studies focused on exploring the role of the intestinal epithelium in IBD were hampered by the lack of techniques for the long-term culturing of human primary epithelial cells ex vivo. Recently, however, a methodology for generating stable human 3D epithelial cultures directly from adult intestinal stem cells was established. These long-term cultures, called organoids, mimic the tissue of origin and can be generated from small-size intestinal tissue samples, making it a promising tool for modeling the course of IBD.In this review, we provide an overview of the versatility of human organoid cultures in IBD modeling. We discuss recent advances and current limitations in the application of this tool for modeling the contribution of the intestinal epithelium alone and in combination with other key cellular and molecular players in the context of IBD pathophysiology. Finally, we outline the pressing need for technically standardizing the laboratory manipulation of human epithelial organoids for their broader implementation in clinically oriented IBD studies.

FIGURE 1.

Human adult epithelial stem cell–derived organoids in inflammatory bowel disease modeling. The healthy gut epithelial barrier (Panel 1, left side of the picture) is a monolayer of columnar cells organized into invaginations called crypts. It represents the interface between the intestinal lumen, containing the gut microbiota on 1 side, and the lamina propria (LP), where immune and mesenchymal cells reside, on the other. Adult stem cells (ASCs) reside at the bottom of each crypt (ASC niche) and continuously give rise to daughter cells that differentiate into the various epithelial subtypes. The disruption of the epithelial layer contributes to both the development and the perpetuation of inflammatory bowel disease (IBD). Injury to the mucosa, which is the hallmark of active IBD, can result from a predisposing genetic and/or epigenetic background (Panel 1, right side of the picture) in some patients, combined with aberrant pro-inflammatory signals from the surrounding luminal and LP environment (Panel 2). Intrinsic mechanisms are then activated within the intestinal mucosa that promote wound healing and thus restore tissue homeostasis (Panel 3). However, permanently disturbed epithelial functions that are not restored during remission may contribute to the persistence of IBD over time (Panel 4). Patient-specific organoid cultures generated from the ASCs of non-IBD and IBD mucosa represent a versatile tool for exploring the role of the epithelium in the diverse IBD-relevant scenarios depicted in the figure (A–C). By using “omics” technologies, for instance, cohorts of pure epithelial cultures (A) can be used to obtain in-depth profiles of the epithelial genetic/epigenetic background or the effect of engineered genetic mutations (Panel 1). Similarly, “omics” approaches can also be applied to organoid cultures to interrogate the effects of this background or of epigenetic marks (acquired from the persistent exposure of the epithelial lining to pro-inflammatory signals) (A) in IBD perpetuation (Panel 4). Alternatively, 3D organoid cultures can be adapted, for example, to a 2D platform, to study the effects of the direct or indirect (eg, through secreted mediators) interactions of the epithelium with the luminal microbiota (B) and LP cells (C) during the different stages of IBD pathophysiology (Panels 2, 3, and 4).