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.
