dc.creator | Saunders, Diane Caitlin | |
dc.date.accessioned | 2020-08-21T21:27:59Z | |
dc.date.available | 2018-03-26 | |
dc.date.issued | 2018-03-26 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-03232018-170107 | |
dc.identifier.uri | http://hdl.handle.net/1803/11179 | |
dc.description.abstract | Regeneration of endogenous β-cells is a promising therapy to treat diabetes, but there are considerable gaps in our understanding of the microenvironmental signals necessary to stimulate β-cell proliferation and the unique ways human β-cells differ from rodents. Our group previously modulated the islet microenvironment using a mouse model in which vascular endothelial growth factor A (VEGF-A) overexpression causes β-cell loss and endothelial cell (EC) expansion, followed by β-cell proliferation and regeneration that requires infiltrating macrophages. To determine the role of proliferative and quiescent ECs, we conditionally inactivated the key receptor mediating VEGF-A signaling, VEGFR2, in ECs and found that EC signaling was necessary for maximal macrophage recruitment and phenotype activation. We also showed that ablation of VEGFR2 in quiescent ECs during the β-cell regenerative phase induced rapid vessel regression that promoted β-cell proliferation, possibly mediated by growth factor release from the extracellular matrix. Extending these findings to human pancreas development, we determined that intra-islet EC area was greatest during the first year of postnatal life and coincided with the peak of β-cell proliferation, suggesting that vascular arrangement or EC-derived signals may impact human β-cell proliferation. Next, to advance the methodologies for studying human islets, we identified two molecular markers of developing and mature human β-cells. Secretory granule membrane major glycoprotein 2 (GP2) marks a population of multipotent pancreatic progenitor cells in the neonatal human pancreas, and can be utilized to improve efficiency of generating β-like cells from stem cells. Nucleoside triphosphate diphosphohydrolase 3 (NTPDase3) is a cell surface marker of adult human β-cells, and is a unique tool for isolating live β-cells by flow cytometry and performing in vivo β-cell imaging. These two markers will further our knowledge of islet development and allow us to assess β-cell gene expression and mass during the disease process, which we demonstrated by utilizing our islet cell isolation strategy to reveal transcriptional dysregulation in α-cells from donors with type 1 diabetes. Together, this work provides a framework for future efforts aimed at promoting β-cell regeneration and increasing functional β-cell mass. | |
dc.format.mimetype | application/pdf | |
dc.subject | β-cell regeneration | |
dc.subject | pancreatic islet | |
dc.subject | endothelial cells | |
dc.subject | microenvironment | |
dc.subject | macrophage recruitment | |
dc.title | Towards Pancreatic β-Cell Regeneration:
Modulating Islet Microenvironment and Identifying Markers of β-Cell Maturation | |
dc.type | dissertation | |
dc.contributor.committeeMember | Antonis Hatzopoulos, Ph.D. | |
dc.contributor.committeeMember | Ambra Pozzi, Ph.D. | |
dc.contributor.committeeMember | Roland Stein, Ph.D. | |
dc.contributor.committeeMember | Alvin C. Powers, M.D. | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Molecular Physiology and Biophysics | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2018-03-26 | |
local.embargo.lift | 2018-03-26 | |
dc.contributor.committeeChair | David Jacobson, Ph.D. | |