Human gastrointestinal organoids as models to study organ development & digestive diseases скачать в хорошем качестве

Human gastrointestinal organoids as models to study organ development & digestive diseases

Presenter: James Wells, Cincinnati Children's Hospital Medical Center, USA From the EMBO | EMBL Symposium: Organoids: Modelling Organ Development and Disease in 3D Culture 21 - 24 October 2020, Virtual ABSTRACT Successful efforts to direct the differentiation of human embryonic and induced pluripotent stem cells (PSCs) into specific organ cell types in vitro have largely been guided by studies of embryonic organ development. For example, by precise temporal manipulation of the signaling pathways that drive anterior-posterior and dorsal-ventral patterning, we can now differentiate human PSCs into a myriad of gastrointestinal organoids including esophageal, gastric fundus, gastric antrum, small intestinal and colonic organoids. GI organoids contain complex epithelial structures and diverse cell types that are unique to their representative organ; esophageal organoids develop a stratified squamous epithelium, gastric organoids have a glandular epithelium that secrete digestive enzymes, and acid, and intestinal organoids secrete mucins and hormones and absorb nutrients. While the first generation of GI organoids had epithelium and mesenchymal derivatives like smooth muscle and myofibroblasts, they were lacking important cell types and functions. However, all GI tissue contain cells that come from the three primary germ layers. The endoderm that gives rise to the epithelium, the mesoderm that gives rise to the smooth muscle and stroma, and the ectoderm that gives rise to the nervous system of the GI. While intestinal and colonic organoids intrinsically contain two of these components, the endoderm/epithelium and the mesoderm/smooth muscle components, they lacked the cells of the enteric nervous system and immune cells. We have now engineered small intestinal organoids with a functional enteric nervous and colonic organoids with functional immune cells capable of triggering an inflammatory cascade in response to pathogenic bacteria. In contrast to intestinal organoids, esophageal and gastric organoids only contain one of the three primary germ layer components, an endodermally-derived epitheliuim.We have now engineered stomach and esophageal tissues containing all three components germ layer components that are each separately derived and then combined. The resulting gastric organoids are structurally complex with glands and organized layers of smooth muscle that contain well organized neuroglial bundles. We are using these to identify new pathologies in patients with complex GI diseases.