Pancreatic disease modelled with human pluripotent stem cellsAlexander Kleger (Ulm University, Germany)
Cell plasticity plays an essential role in chronic pancreatitis, human pancreatic cancer (PDAC) and development of diabetes. The morphological processes are closely related to molecular programs known from early embryonic development of the pancreas. Based on these analogies, we have developed new disease models to decipher the causes of the aforementioned pathophysiologies and to design innovative, personalized therapies. One of the core areas in the lab is pancreatic differentiation of human pluripotent stem cells (hPSC). Here, we have differentiated hPSCs into pancreatic duct-like organoids (PDLOs) with morphological, transcriptional, proteomic, and functional characteristics of human pancreatic ducts, further maturing upon transplantation into mice. This model enabled in vitro and in vivo studies of pancreatic plasticity, dysplasia, and cancer formation from a genetically defined background. Using similar models, we also approached the endocrine lineage and revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. In this seminar, I will summarize these seminal papers and give an overview about our unpublished efforts to model pancreatic disorders.
Invited by Cécile Julier