NEURAL CONTROL OF ENDOCRINE CELL DEVELOPMENT IN THE HUMAN PANCREAS

Inadequate insulin production and secretion from pancreatic beta (β) cells cause  type 2 diabetes (T2D), a disease afflicting 400 million people.

Genomewide association studies have identified >250 T2D gene loci, many of these genes are expressed in adult pancreatic islets, indicating that defects in β cell function, number, and islet architecture contribute to the disease.

Pancreatic islets containing α and β cells are produced during fetal development, thus defects in islet differentiation may contribute to T2D heritability.

Our current knowledge of pancreas development is based on animal studies, showing that signals from blood vessels, nerves, and mesenchyme control islet formation.

However, significant differences between human and mouse islet cell development and innervation have been observed suggesting that studies using human pancreas anlagen are required to understand human β cell differentiation and the impact of diabetes risk alleles on islet development.

We aim to determine how 1) the human pancreas becomes innervated, 2) novel T2D risk alleles affect differentiation of human β cells and 3) pancreatic nerves control islet formation.

We will use single cell transcriptomics, whole mount imaging, and iPSC differentiation to determine how pancreatic innervation and T2D risk alleles affect β cell development, providing novel insight into diabetes heritability and improve differentiation protocols for islet cell replacement therapy.