Identification of a small molecule that facilitates the differentiation of human iPSCs/ESCs into pancreatic endocrine cells. Homo sapiens

Pancreatic beta cell generation from induced pluripotent stem cells (iPSCs) offers an alternative donor tissue source; however, the efficiency of induction of INSULIN (INS)+ cells from human iPSCs (hiPSCs) is low. We aimed to establish an efficient differentiation protocol for generating INS+ cells from hiPSCs by identifying novel inducers. We screened small molecules that increased the induction rate of INS+ cells from hiPSC-derived PDX1+ pancreatic progenitor cells by using high-throughput screening (HTS) system. We identified one compound, sodium cromoglicate (SCG) out of about 1,250 small molecules that we screened. When SCG was combined with the previously described protocol, the induction rate of INS+ cells increased up to 15–20%, and the cells developed the ability to secrete C-peptide in vitro. We found that SCG facilitates the differentiation of multiple endocrine cell types, including INS+ cells, in both hiPSC differentiation cultures and mouse embryonic pancreas explants by inducing NEUROG3+ endocrine precursor cells. We also confirmed that the mechanisms of action by which SCG induces the pancreatic endocrine differentiation include the inhibition of BMP4 signaling. Overall design: We performed RNA sequencing analyses to compare the gene expression profiles of cells that were differentiated from hiPSC-derived PDX1+ PP cells after 8 days of treatment with SCG and those that were treated with H2O (control); we also compared the gene expression profiles of cells that were treated with 4Fs and SCG and those that were treated with 4Fs alone.