Patient-derived organoids for therapy personalization in inflammatory bowel diseases

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract that have emerged as a growing problem in industrialized countries. Knowledge of IBD pathogenesis is still incomplete, and the most widely-accepted interpretation considers genetic factors, environmental stimuli, uncontrolled immune responses and altered intestinal microbiota composition as determinants of IBD, leading to dysfunction of the intestinal epithelial functions. In vitro models commonly used to study the intestinal barrier do not fully reflect the proper intestinal architecture. An important innovation is represented by organoids, 3D in vitro cell structures derived from stem cells that can self-organize into functional organ-specific structures. Organoids may be generated from induced pluripotent stem cells or adult intestinal stem cells of IBD patients and therefore retain their genetic and transcriptomic profile. These models are powerful pharmacological tools to better understand IBD pathogenesis, to study the mechanisms of action on the epithelial barrier of drugs already used in the treatment of IBD, and to evaluate novel target-directed molecules which could improve therapeutic strategies. The aim of this review is to illustrate the potential use of organoids for therapy personalization by focusing on the most significant advances in IBD research achieved through the use of adult stem cells-derived intestinal organoids.

Keywords: 3D cell cultures; Inflammatory bowel disease; Intestinal epithelium; Organoids; Personalized medicine.

Figure 1

Intestinal organoid in inflammatory bowel disease research: The future of precision medicine. Patient-derived intestinal organoids are three-dimensional in vitro cell structures derived from stem cells that differentiate and self-organize into functional intestinal epithelium-specific cell types. For this reason, this model is suitable for different research approaches useful to inflammatory bowel disease (IBD) modelling and to study current and new therapeutic options. By retaining the disease-specific phenotypic defects, intestinal organoids can be employed to study epigenetic and transcriptomic profiles. In addition, the ability of intestinal organoids to differentiate into all the different cell types present in the intestinal epithelium makes this model useful to discover new cell-specific disease mechanisms. Furthermore, organoids can be used to study cytokine-induced apoptosis and to test currently used drugs to better understand their mechanisms. Co-culturing intestinal organoids with either microbiota components or immune cells helps to investigate IBD pathogenesis. Thanks to all these research approaches new pharmacogenomic biomarkers, new therapeutic targets and new drugs could be discovered, enabling the development of precision medicine for IBD patients. The image was created with https://biorender.com/.