Abstract

Type 1 diabetes is an autoimmune disease characterized by destruction of insulin-producing beta cells within the pancreatic islets and loss of blood sugar homeostasis. A major focus for treatment is beta cell replacement therapy to restore blood sugar control. While recent advances in the generation of islet cells from human stem cells have catapulted the field forward, important challenges remain, including relatively low purity of the differentiated cells, suboptimal functional maturity, and the production of undesired cell types. Islet endocrine cells (including beta cells) derive from a common precursor, called an endocrine progenitor cell, during pancreas development. The action of molecular machines called transcription factors play a key role in the development of beta cells, but much is still unknown about the precise molecular roles of transcription factors in this critical progenitor-to-beta cell transition. Our goal is to better understand how transcription factors drive the genetic and epigenetic forces that produce beta cells during human pancreas development. We will use advanced sequencing, bioinformatic techniques, and dynamic functional characterization to reveal at high cellular resolution how transcription factors regulate the molecular inner workings and function of human beta cell development. These studies aim to reveal key molecular mechanisms of beta cell development to further refine the generation of the stem cell-derived beta cells used in diabetes treatment.