Emergent Behaviors of Integrated Cellular Systems (EBICS) Distinguished Lecture

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“Pluripotent Stem Cell-derived Gastrointestinal Organoids as New Models to Study Human Development and Disease”

James Wells, Ph.D.
Chief Scientific Office, Center for Stem Cell and Organoid Medicine (CuSTOM)
Director for Research, Division of Endocrinology
Cincinnati Children’s Hospital

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. We have used principles of organogenesis to generate complex, three-dimensional human gastrointestinal organ tissues from PSCs in vitro. We have done this by focusing on the signaling pathways that drive anterior-posterior and dorsal-ventral patterning of the developing endoderm. We can now generate organoids representing all of the organs of the gastrointestinal tract including esophagus, gastric fundus, gastric antrum, small intestine and colon. 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, hormones, and acid, and intestinal organoids additionally absorb nutrients. While the first generation of GI organoids had epithelium and mesenchyme, they were lacking important cell types and functions. We have now engineered additional cellular complexity into organoids, such as 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. Ongoing studies include PSC-derived organoids to identify the underlying mechanisms behind birth defects including Hirschsprung’s disease and esophageal atresia, to identify new pathologies in patients with complex GI diseases. Lastly we are using human organoids to investigate the how the GI endocrine system modulates a broad array of metabolic functions including nutrient sensing and absorption.

NIH grant funding: P01HD093363, U01DK103117, U19 AI116491, UG3DK119982


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