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dc.contributor.advisorLee, Richard
dc.contributor.advisorMichel, Thomas
dc.contributor.advisorKissler, Stephan
dc.contributor.advisorMostoslavsky, Gustavo
dc.contributor.authorDavis, Jeffrey
dc.date.accessioned2019-12-12T09:06:00Z
dc.date.created2019-05
dc.date.issued2019-05-16
dc.date.submitted2019
dc.identifier.citationDavis, Jeffrey. 2019. Functional Maturation and Glucose Responsiveness in Stem Cell-Derived β Cells. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42029721*
dc.description.abstractStem Cell-derived β cells (SC-β cells) are an unlimited source of islet-like material for curative transplantation in patients with Type 1 Diabetes. SC-β cell potential to supplement or replace human islets for transplantation is limited by their ability to sense changes in glucose levels and respond by secreting insulin to restore normoglycemia. SC-β cells respond to glucose in vitro, but at a magnitude lower than that of human islets. We have analyzed their capability to sense glucose and undergo glucose stimulated insulin secretion (GSIS) in vitro and identified a novel bottleneck in glycolysis, limiting their potential to undergo GSIS. Bypassing this deficiency in metabolism results in an insulin secretion profile indistinguishable from human islets. SC-β cell glucose sensing also improves after transplantation. To study this process, we have analyzed gene expression changes before and after transplantation into immune-compromised mice. In addition to identifying changes in pathways regulating insulin secretion, we have identified Islet Amyloid Polypeptide (IAPP) as a potential marker of more mature SC-β cells. Using a dual knock-in fluorescent reporter line, we have characterized the dynamics of the IAPP-expressing SC-β cell subpopulation before and after transplant, demonstrating IAPP expression marks a more mature, stable population of SC-β cells in vitro. In summary, we have identified a glycolytic defect in SC-β cells limiting their function in vitro. Bypassing this defect will assist in generating SC-β cells for cell-based therapies for diabetic patients. Analysis of gene expression during in vivo functional maturation of SC-β cells revealed IAPP expression is characteristic of more mature SC-β cells in vitro and has provided a new marker for SC-β cells during differentiation.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjecttype 1 diabetes
dc.subjecttype 2 diabetes
dc.subjectstem cell-derived β cells
dc.subjectglucose stimulated insulin secretion
dc.subjecthuman embryonic stem cells
dc.subjectinduced pluripotent stem cells
dc.subjectinsulin
dc.subjectislet amyloid polypeptide
dc.subjectamylin
dc.subjectmaturation
dc.subjectmetabolism
dc.subjectcarbon tracing
dc.titleFunctional Maturation and Glucose Responsiveness in Stem Cell-Derived β Cells
dc.typeThesis or Dissertation
dash.depositing.authorDavis, Jeffrey
dc.date.available2019-12-12T09:06:00Z
thesis.degree.date2019
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.type.materialtext
thesis.degree.departmentMedical Sciences
thesis.degree.departmentMedical Sciences
dash.identifier.vireo
dash.author.emailjeffrey.davis25@gmail.com


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