iPSC-derived pancreatic progenitors are an optimal model system to study T2D regulatory variants active during fetal development of the pancreas

Pancreatic progenitor cells (PPCs), which are multipotent cells that have the potential to give rise to endocrine, exocrine and epithelial cells, provide a powerful model system to examine the molecular characteristics of differentiating, fetal-like pancreas cells and to study the genetics of pancreatic disease. We differentiated ten induced pluripotent stem cell-derived pancreatic progenitor cell (iPSC-PPC) lines and, using single cell RNA-seq and single nuclear ATAC-seq, we found that they show varying levels of cellular maturity, including the presence of early PPC, endocrine and exocrine cells. We evaluated iPSC-PPC as a model system to study type 2 diabetes (T2D) and found that, of 380 T2D risk loci, 208 overlapped regulatory elements active in iPSC-PPC, including 55 fetal-specific. These loci are associated with transcription factor binding site alterations and allele-specific expression, suggesting that iPSC-PPC are an optimal model system to annotate GWAS variants that are not functional in the adult pancreas.