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Title page for ETD etd-07162015-063532


Type of Document Dissertation
Author Aamodt, Kristie Irene
URN etd-07162015-063532
Title Macrophages and Endothelial Cells in the Pancreatic Islet Microenvironment Promote β Cell Regeneration
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Ambra Pozzi Committee Chair
Alyssa H. Hasty Committee Member
Pampee P. Young Committee Member
Roland W. Stein Committee Member
Keywords
  • beta cell regeneration
  • macrophage
  • endothelial cell
  • diabetes
Date of Defense 2015-06-24
Availability restricted
Abstract
Reduced pancreatic β cell mass is a hallmark of diabetes, which makes the ability to increase or restore β cell mass a major therapeutic goal. While testing the hypothesis that increased endothelial cell signaling would increase β cell mass using a model of inducible vascular endothelial growth factor-A (VEGF-A) overexpression in β cells (βVEGF-A mouse), we found that increased VEGF-A leads to reduced, not increased, β cell mass. Surprisingly, withdrawal of the VEGF-A stimulus is followed by robust β cell proliferation, leading to islet regeneration, normalization of β cell mass, and reestablishment of the intra-islet capillary network. Using islet and bone marrow transplantation approaches we found that β cell proliferation is dependent on the local microenvironment of endothelial cells, β cells, and bone marrow-derived macrophages recruited to the islets upon VEGF-A induction. Depleting macrophages greatly reduced β cell proliferation, indicating that these macrophages are required for the β cell proliferative response in regenerating islets. Based on these data, in addition to transcriptome analysis of FACS-sorted islet β cell, and islet-derived endothelial cell and macrophage populations during VEGF-A induction and normalization, we propose a new paradigm for β cell regeneration where β cell self-renewal is mediated by coordinated interactions between macrophages recruited to the site of β cell injury, intra-islet endothelial cells, and β cells. In this model, (1) increased growth factors produced by β cells, endothelial cells, macrophages, (2) increased production of growth factor receptors and integrins on β cells, and (3) increased integrin activation by the extracellular matrix cause simultaneous, and potentially synergistic, activation of the PI3K/Akt and MAPK signaling pathways, leading to β cell proliferation.
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