Modeling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary

Organogenesis is a complex and inter-connected process, orchestrated by multiple boundary tissue interactions(1–7). However, it is currently unclear how individual, neighboring components coordinate to establish an integral multi-organ structure. Here, we report the continuous patterning and dynamic morphogenesis of hepatic, biliary and pancreatic structures, invaginating from a three-dimensional culture of human pluripotent stem cell (PSC). The boundary interactions between anterior and posterior gut spheroids differentiated from human PSCs enables autonomous emergence of hepato-biliary-pancreatic (HBP) organ domains specified at the foregut-midgut boundary organoids in the absence of extrinsic factor supply. Whereas transplant-derived tissues were dominated by midgut derivatives, long-term culture of micro dissected HBP organoids develop into a segregated hepato-pancreato-biliary anlage, followed by the recapitulation of early morphogenetic events including the invagination and branching of three different and inter-connected organ structures, reminiscent of tissues derived from mouse explanted foregut-midgut culture. Missegregation of multi-organ domains incurred by a genetic mutation in HES1 abolishes the biliary specification potential in culture, as seen in vivo(8,9). Together, we demonstrate that the experimental multi-organ integrated model can be established by the juxta-positioning of foregut and midgut tissues, and potentially serves as a tractable, manipulatable and easily-accessible model for the study of complicated endoderm organogenesis in human.