Human organoids: a model system for intestinal diseases

You are what you eat. A common saying that indicates that your physical or mental state can be influenced by your choice of food. Unfortunately, not all people have the luxury to choose what to eat; this can be related to place of birth, social, economic state, or the physical inability of the diseased intestine to take up certain food. A cell layer, the epithelium, covers the intestine, and harbors the main functions of the intestine: uptake, digestion of food, and a barrier against unwanted guests from outside the body. The intestinal epithelium consists of protrusions (villi) and invaginations (crypts) and all cells are renewed every four to five days. This renewal is possible because the stem cell, residing in the crypt, multiplies and produces all specialized epithelial cells. The group of Hans Clevers discovered a method to isolate these crypts, including the stem cells, and by adding growth factors, they were able to maintain these cells in a culture dish for weeks. These mini-intestines, which are grown in the lab, are called organoids and can be made from a small part (biopsy) of the intestine from a patient. The aim of this thesis was to make these organoids from patients with intestinal diseases, and to see if they recapitulate the patient’s intestine and are a useful model for studying intestinal diseases. Chapter 2 of this thesis focuses on the healthy intestine, the intestinal stem cell and location-specific properties. In chapter 3, we report our discovery of a new gene mutation for MVID, syntaxin 3. In chapter 4 we elaborate on these STX3 patients and the function/dysfunction of their intestine. In chapter 5, we study cystic fibrosis and use orga¬noids as a model to set up a forskolin-swelling assay that can help to predict patient-specific response on drugs. In chapter 6, we use organoids to discuss the role of the epithelium in celiac disease. At the end of this thesis we will evaluate if organoids, used as intestinal model in all chapters, truly recapitulates the in vivo epithelium and discuss possible applications and recommendations for this model.