A coherent roadmap to generate either pancreatic acinar or duct-like cells from human pluripotent stem cells challenges pancreatic cancer biology

Cell bioengineering approaches not only hold great promise to replace and regenerate dysfunctional tissue for improved life quality of the diseased patient but may also provide more sophisticated disease models. Engineering approaches to build human pancreatic tissue resembling acinar, ductal and endocrine tissue have been hampered by the complexity of the pancreas. Human pluripotent stem cells (PSCs) may provide the appropriate bioengineering platform for developmental and biomedical studies due to their capability to differentiate into every cell type in the human body. However, PSCs typically yield heterogeneous population, while certain disease models require homogenous populations. Our initial protocol was powered to generate virtually pure cultures of human pancreatic progenitor cells followed by spontaneous differentiation in a 3D-culture environment to allow acinar ductal commitment (Hohwieler, GUT, 2017). Here, we have implemented signals controlling embryonic lineage fate bifurcations to efficiently yield the desired cell types through exclusion of alternate fates: Specifically, we applied signaling molecules and growth factors inducing either acinar or ductal cells, while inhibiting the respective counter lineage with inhibitors. This approach yields virtually pure pancreatic acinar or duct-like cells generated from human PSCs resembling key features of adult human pancreatic counterparts as shown in an established test battery. Thereby, we provide a coherent roadmap to generate the two mature exocrine pancreatic cell types, acinar and ductal cells. Finally, we have applied this novel tool box to dissect the cell type of origin of pancreatic cancer.