Changes in Human Islet Microvasculature during Type 1 Diabetes
Contact PI: Joana Almaca, PhD
Start Date: June 1, 2018
HIRN New Investigator Award Recipient
Endocrine cells in pancreatic islets are embedded in a network of microvessels that regulate islet blood flow and hormone secretion (1). It is still not known what happens to the islet microvasculature in type 1 diabetes (T1D), despite being the site of immune cell recruitment and infiltration. The microvasculature consists of capillary tubes made of a thin layer of endothelial cells covered by pericytes. Pericytes, the mural cells of the microcirculation, are crucial for proper microvascular function, by giving structural stability, participating in angiogenesis, controlling vascular permeability and blood flow (2). While a wide body of literature exists on islet endothelial cells, the function of the islet pericyte is largely unknown (3). The aim of this research project is to look at pericytes in islets from non-diabetic donors as well as in individuals at different stages of type 1 diabetes. The hypothesis is that abnormal pericyte coverage of islet capillaries causes microvascular dysfunction and contributes to the development of T1D. This hypothesis will be tested following two specific aims. In specific aim 1, I propose to analyze the structure of human islet capillaries and their mural cell coverage during the progression to T1D by immunohistochemistry and electron microscopy. Pericyte coverage and density will be correlated with the presence of leucocytes, endothelia adhesion molecules, extracellular matrix proteins, and residual beta cell mass. I will also relate microvascular alterations with hyperglycemia and other key pathological features of T1D. In specific aim 2, I will determine if pericytes control human islet capillary diameter, similar to their role in mouse islets (4). Using living human pancreas tissue slices, changes in islet capillary diameter (labeled with fluorescent lectins) and cytosolic Ca2+ levels in pericytes (that have incorporated a Ca2+ indicator, e.g. Fluo4) can be simultaneously recorded in response to vasoactive substances by time-lapse confocal microscopy. Microvessel and pericytes’ responses in non-diabetic donors will be compared with those from donors with T1D. Because vascular cells can strongly impact beta cell performance, exploring how these change during T1D may challenge our understanding of the pathogenesis of this disease.
Literature cited: (1) Ballian, N. & Brunicardi, F.C. World journal of surgery 31, 705-714 (2007); (2) Armulik, A., et al. Developmental cell 21, 193-215 (2011);
(3) Jansson, L., et al. Upsala journal of medical sciences 121, 81-95 (2016); (4) Almaça, J., et al. Cell Metabolism 27, 630-644 (2018).