Islet transplantation is the only established cell-based therapy for treating diabetes. However due to the limited availability of pancreas and low yield of islets isolated, it is important to find alternate sources of potential insulin-producing cells. We are the first to identify insulin-producing cells in human gallbladder epithelium. Although, the levels of pro-insulin transcripts in the galbladder are thousand-fold less than those in pancreatic islets, this level of expression is significantly higher than that identified in any stem/progenitor cells. Insulin-producing cells have also been identified in brains of flies, mice and in a clinical case of insulinoma in patient with congenital brain malformation.

We believe that a better understanding of transcriptome, epigenome and microRNome in all these (brain, gallbladder and pancreatic) insulin-producing cells will provide vital cues towards understanding an ‘expressome’ of insulin-producing cells. Generation of such expressome maps will also guide the differentiation of other human progenitors to insulin-producing cells.

We plan to use a range of molecular techniques to characterize these cells. These include Next Generation Sequencing(NGS), TaqMan-based real-time PCR, immunocytochemistry, single-cell PCR, Chromatin-IP(ChIP) and DNA methylation to map the transcriptome and epigenome expression of islets, GB and brain cells.

Our NGS and qPCR analyses indicate similarities between the transcriptome in the brain, gallbladder and pancreatic islets (Figure 1). Differences between expression of key transcription factors includes Pdx1, which is expressed in gallbladder at ~50% of the abundance seen in human islets. Expression of the glucose transporter Glut1 is significantly higher in human islets than Glut2 at comparable levels in human gallbladder. Urocortin-3, associated with insulin-producing cell maturation was ~8-fold lower in human gallbladder than islets and around 20-fold lower in brain. MiRNAs involved in pancreatic beta-cell function are expressed in human gallbladder (correlation, R2 =0.716). ChIP data for H3K4-me3 indicate that gallbladder epithelial progenitors continue to retain open chromatin conformation.

These studies demonstrate that although islets undoubtedly represent “factories” of insulin-producing cells, understanding the expressome in human gallbladders and brain cells will complement already existent epigenetic and transcriptomic maps in rodent islet development and potentially guide human stem/progenitor cell differentiation, for cell replacement therapy in diabetes.