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.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07162015-063532 |
| Date | 16 July 2015 |
| Creators | Aamodt, Kristie Irene |
| Contributors | Ambra Pozzi, Alyssa H. Hasty, Roland W. Stein, Pampee P. Young |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-07162015-063532/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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