Publication

Engineering healthy human pancreatic duct-like organoids for disease-modeling

Confocal section through a cluster of fully differentiated human ductal organoids, depicted by immunofluorescence for E-cadherin (green) and Cytokeratin 19 (red).

A new study in Cell Stem Cell models the plasticity and dysplasia of the human pancreas in iPSC-derived pancreatic ductal organoids.

 

The fundamental insights into cellular reprogramming that earned Shinya Yamanaka and Sir John Gurdon the 2012 Nobel prize opened a conceptual window for many scientists to generate a variety of human disease models in a dish.
An international research consortium, led by Prof. Alexander Kleger from the Department of Internal Medicine I at the University Hospital in Ulm, Germany and his Co-Principal Investigators on this study Dr. Meike Hohwieler (University Hospital Ulm, Germany) and Dr. Matthias Meier (Helmholtz Pioneer Campus at Helmholtz Munich, Germany), reports in the prestigious journal Cell Stem Cell on the generation of a highly robust and reproducible platform for the differentiation of human pluripotent stem cells (hPSC) into pancreatic ductal organoids.

The paper sets itself apart from many other studies within the ‘organoid for disease modeling’ field due to the developmental trajectory-inspired optimization of its stem cell differentiation protocol. Painstakingly and reiteratively, the authors engineer and molecularly validate ductal organoids, to reach an unprecedented level of cellular purity. Their work is guided by extensive transcriptomic and proteome analyses, revealing most current and decisive developmental markers of the human pancreatic ductal fate. Ultimately, the authors arrive at a mature exocrine pancreas lineage that genuinely recapitulates human physiology, e.g. producing digestive enzymes and mucus.


"All in all, our study makes an extremely compelling case that the newly developed platform readily reproduces the genetic, phenotypic and molecular-mechanistic underpinnings of genetically triggered ductal malignancies",
state the three, senior authors of the study.



Reaching further, the team corroborates the functional relevance of their new platform for disease modeling – by using two distinct oncogenic mutations that induce the broad spectrum of most common malignant features of both pancreatic ductal adenocarcinoma and McCune-Albright patients. Most convincing, in-vivo corroboration comes from extensive validations in heterotopic transplantation experiments.
‘All in all, our study makes an extremely compelling case that the newly engineered organoid platform readily reproduces the genetic, phenotypic and molecular-mechanistic underpinnings of genetically triggered ductal malignancies’ state the three, senior authors of the study, in highlighting the value of their work for an accelerated understanding of processes that govern the normal developmental trajectory of the human pancreas as well as for the development of novel and personalized clinical avenues to treat particularly pancreatic cancers.  
Together, the work provides exceptional value for the developmental biologist community through ultimately making currently uncharacterized processes of exocrine pancreas development in mouse and humans readily accessible. More intriguing, the study adds important clinical value, providing clinician-scientists worldwide with a novel and very powerful differentiation pipeline to functionally understand - and eventually prevent - the rapid progression of devastating pancreatic ductal adenocarcinomas, that are estimated as the second most common cause of cancer-related deaths in the Western World by 2030.

 

 

 

Link to the original article: www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00111-9

Link to PR from Ulm University (in German) www.uni-ulm.de/med/fakultaet/med-detailseiten/news-detail/article/bauchspeicheldruesen-tumore-aus-dem-labororganoide-helfen-die-krebsentstehung-zu-verstehen/