Hiroyuki Koike 1 , 2 , Kentaro Iwasawa 1 , 2 , Rie Ouchi 1 , 2 , Mari Maezawa 1 , 2 , Kirsten Giesbrecht 1 , 2 , Norikazu Saiki 6 , Autumn Ferguson 1 , 2 , Masaki Kimura 1 , 2 , Wendy Thompson 1 , 2 , James M. Wells 2 , 3 , 4 , 5 , Aaron M. Zorn 2 , 3 , 5 , Takanori Takebe 1 , 2 , 3 , 5 , 6
25 September 2019
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.