Functional gene regulatory networks and broad applications of the human expandable pancreatic progenitor-islet system [scRNA-Seq]

Investigating the precise gene regulatory programs directing pancreatic differentiation provides insights into the mechanisms of pancreatic development and diabetes progression. Here, we performed integrated single-cell multi-omic analyses of the expandable pancreatic progenitor (ePP)-islet system. We defined the dynamic transcriptomic and chromatin landscapes of pancreatic differentiation, inferred the sophisticated gene regulatory networks (GRNs) that govern ePP self-renewal, endocrine specification and islet function, and identified the essential roles and interesting mechanisms of the NKX2.2-CLEC16A/endosomal pathway axis during cell-fate transitions. We have obtained interesting observations that are human specific not observed in mouse models (e.g., CLEC16A-related diabetes mechanisms), and further took advantage of the ePP-islet system to identify pharmacological rescuers. Notably, this study highlights the ePP-islet system as a very powerful platform for uncovering the molecular mechanisms of cell fate decision and rich information for further optimizing the differentiation process. With further optimization and better understanding, the ePP-islet system will undoubtedly have very broad applications, including disease modeling, drug discovery, and regenerative medicine.