Anders Hedin: A transcriptomic exploration of the human pancreas

Abstract

The pancreas is organ with two functionally distinct compartments: The endocrine islets of Langerhans and the exocrine tissue consisting of the secretory acini and their associated ducts. The pancreas is the main organ involved and common and severe diseases such as diabetes mellitus, pancreatitis and pancreatic cancer. This thesis contains 4 papers in which RNA- sequencing based approaches are applied to study the pancreatic microenvironment and how it is shaped by complex interactions between endocrine, exocrine, vascular, and immune cell populations. 

In paper I we show that islet endothelial cells are transcriptionally distinct from exocrine endothelial cells, exhibiting strong enrichment of angiogenic and VEGF-associated pathways, consistent with the highly vascularized endocrine niche. In Paper II, we demonstrate data that suggests that pancreatic macrophages segregate into two major populations defined by CD206 expression, with CD206⁺ macrophages displaying immune-regulatory and homeostatic gene programs and CD206⁻ macrophages showing proliferative and metabolically active profiles; and that these differences exceeded those attributable to tissue compartment or glycaemic status. In Paper III we analyse laser capture microdissection isolated islet tissue from individuals with or without type 1 diabetes. The analysis revealed extensive transcriptional remodelling beyond β-cell loss, including upregulation of vascular and angiogenesis-related pathways which is supported by immunofluorescence data supporting an increased islet vascular density. In paper IV we use spatial transcriptomics to examine regions of the pancreas in T1D and non- diabetic controls. Our results suggest a dysregulated protein response and a state of de- differentiation in beta cells in long standing T1D, as well as profound perturbation in acinar and ductal cells. 

The main findings of this thesis thus demonstrate pronounced cell-type–specific heterogeneity within the human pancreas and highlight coordinated vascular and immune remodelling as key features of islet physiology and diabetes pathophysiology.