Investigating the Molecular Regulation of PDX-1 in the Generation of New Insulin-Producing β-Cells from Stem Cells/Progenitor Cells

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Diabetes mellitus is categorized based on the dysfunction (type 2) or loss (type 1) of beta cells. Central to understanding diabetes is the transcription factor PDX-1, which is crucial for pancreas development and beta cell function in adults. Gaining insight into PDX-1's molecular regulation could aid in producing induced pluripotent stem cell-derived mature beta-cells and facilitate the transdifferentiation of various cell types into beta cells. This research explores the post-translational regulation of endogenous or overexpressed PDX-1 via proteasomal or lysosomal machinery.

Using Mass Spectrometry, ISG15 was identified as a novel PDX-1 interactor. The study then delved into the impact of ISG15 on PDX-1's stability and function across cell lines and iPSC-derived beta cells. High-throughput imaging of human tissues illuminated their association in type 2 diabetes and cancer. Key findings included the proteasomal degradation of PDX-1 in specific cell lines and human pancreatic progenitors. Also, the influence of ISG15 on PDX-1 stability varied based on its origin (overexpressed vs. endogenously induced). Increased levels of ISG15 and nuclear PDX-1 proteins were observed in PDAC, while type 2 diabetic cells had elevated ISG15 and insulin.

In summary, this study sought to uncover new PDX-1 regulatory pathways in mature and iPSCs, aiming to advance cell therapies for diabetes and shed light on PDX-1's role in type 2 diabetes and cancer. The results indicate that ISG15's effects on PDX-1 are context-dependent and may play a role in pancreatic diseases.
Date of Award1 Nov 2023
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorRocio Sancho (Supervisor), Karen Liu (Supervisor) & Nikolay N Ninov (Supervisor)

Cite this

'