The morphogenetic plasticity of adult pancreatic islets of Langerhans has been implicated in the development of pancreatic adenocarcinomas and in islet transplant failure. The objective of this doctoral work was to investigate the extent of this plasticity and to characterize the unknown cell types and intracellular mechanisms involved in changes of adult islet phenotype. / In the first published study, isolated adult canine islets were induced to undergo a phenotypic switch into highly proliferative duct-like structures through a two-stage process entailing beta-cell death and the dedifferentiation of the resulting cells. The transformed islets were no longer immunoreactive for islet cell hormones, but now expressed markers of pancreatic duct epithelial cells. Pharmacologic inhibition of signal transduction demonstrated that the balance in signalling activity between ERK/Akt and JNK/caspase-3 appears to be an important regulator of islet cell death and differentiation. / In the second published study, quiescent adult human islets were induced to undergo a similar phenotypic switch into highly proliferative duct-like structures in a process that implicated glucagon- and somatostatin-expressing cells, and was characterized by a loss of expression of islet-specific hormones and transcription factors as well as a temporally-related rise in expression of markers of stermness and duct epithelium. Short-term treatment of these primitive duct-like structures with the islet neogenic factor INGAP 104-118 induced their scalable reversion back to islet-like structures in a P13-kinase-dependent manner. These neoislets resembled freshly isolated human islets with respect to the presence and topological arrangement of the four endocrine cell-types, islet gene expression and hormone production, insulin content and glucose-responsive insulin secretion. The demonstration that adult human islets are able to regenerate themselves establishes a new paradigm in the context of tissue regeneration and diabetes therapy. / These original findings may have important clinical implications for understanding and controlling pancreatic carcinogenesis and islet neogenesis in the adult human pancreas.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85920 |
| Date | January 2005 |
| Creators | Jamal, Al-Maleek |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Surgical Research.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002261201, proquestno: AAINR21657, Theses scanned by UMI/ProQuest. |
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