UCSF

The pancreas is a branched, lobular organ consisting of multiple cell types in two separate tissue compartments that work in concert to maintain proper food digestion and glucose homeostasis. The exocrine compartment synthesizes and secretes digestive enzymes that are shuttled to the intestine, while the endocrine compartment produces various hormones that enter the bloodstream and modulate systemic blood glucose levels. In this work, we sought to understand the diversity of cell types found in the human and mouse pancreas during fetal development. We start in Chapter 2 by performing single-nucleus Assay for Transposable Chromatin Sequencing (snATAC-Seq) on embryonic murine pancreas and construct gene regulatory networks of the developing endocrine and mesenchymal compartments. We uncover candidate TF regulators and downstream target genes of cell fate decisions across developmental time and confirm the expression of identified transcription factors. In Chapter 3, we identify novel and known cell types within the developing human fetal pancreas and their underlying transcriptomic profiles by utilizing single-cell RNA-Sequencing. We undercover significant cellular diversity in all cell types of the human fetal pancreas (endocrine, exocrine, mesenchymal, immune, neuronal and endothelial) and map the cell-cell interactions between these cell types. In the endocrine compartment, we identify novel endocrine progenitor cell types with varying differentiation potency and reconstruct their differentiation trajectories in silico. We then combine our transcriptional knowledge of human fetal pancreas development with chromatin landscape data through snATAC-Seq, allowing for a multi-omic analysis to construct gene regulatory networks and identification potential regulators of cell fate in the human fetal endocrine pancreas. With the chromatin landscape information from our snATAC-Seq data, we also identify development-enriched single nucleotide polymorphisms from genome wide association studies of type 1 and type 2 diabetes. Additionally, we elucidate the cellular composition of in vitro stem cell-derived endocrine cells, identifying the transcriptional control of mis-differentiated populations. Lastly, we identify the transcription factor FEV as a regulator of beta cell differentiation, confirming in silico predictions. Together, we describe a novel in-depth transcriptional and epigenomic understanding of human and mouse pancreas cells, providing a rich database for the field and expanding upon our understanding of pancreas development.