PROJECT SUMMARY The overall goal of the Pluripotent Stem Cell and Organoid Core of the Digestive Health Center (DHC) is to provide DHC investigators with fully integrated services to catalyze research on mechanisms of digestive diseases via innovative and reliable model systems using native and genome edited stem cells and organoids. The Core pursues this goal with four complementary aims. In the First Aim “to provide DHC investigators with human iPSCs and iPSC-derived organoids and training,” the Core makes available to users quality-tested human pluripotent stem cells (PSCs) and PSC-derived multilineage cellular organoids of the esophagus, fundic and antral regions of the stomach, intestine, colon, and liver. The Core also facilitates the production of tissue- derived enteroids and liver and biliary organoids. These are novel 3D-miniature organs that enable studies related to physiology and pathobiology relevant to humans. Core leaders and experienced staff hold technology transfer through formal tiered courses and hands-on training, supervision, and support. In the Second Aim “to provide next generation organoid technologies for cheaper, scalable, high-quality organoids,” the Core provides investigators with the opportunity to generate organoids from healthy or diseased subjects using novel, reliable protocols for more efficient and scalable directed differentiation of human PSCs into organoids. In the Third Aim “to provide services for CRISPR-Cas9 mediated genome editing of human PSCs,” the Core evolved in its scope of technology and service to offer DHC Investigators state-of-the-art genome editing using CRISPR/Cas9 system. Successful projects have used knockin and knockout editing to study mechanisms of disease. To be able to track and visualize these cells in experimental assays, the Core also provide reporter-labeled PSC-editing and screening services to establish novel cell lines based on investigators’ needs. And in the Fourth Aim “to bank and make available quality-controlled iPSC lines and organoids for digestive research,” the Core banks well phenotyped natural and edited hPSC lines as well as disease-specific iPSCs to catalyze the translation of basic research findings into novel diagnostic and therapeutic tools. The service is aligned with high quality metrics and meets regulatory requirements for de- identification and human subject protection. Collectively, these novel technologies empower DHC investigators to study mechanisms of disease using multi-cellular experimental systems that have direct “lineage” to normal and diseased human tissues (including at different stages of maturation). The delivery of services is streamlined and centralized, and positions investigators to explore new collaborative projects to catalyze discoveries that will positively impact digestive disease research.