Signals that control beta cell formation and survival in injured mouse pancreas

Scriptie/Masterproef: Doctoral Thesis

Samenvatting

Current diabetes research focuses on replacing or regenerating the lost
insulin producing beta cell mass. These therapies depend on the
identification of signals and signaling pathways that regulate beta cell
survival, cycling and neogenesis. Partial duct ligation is a surgically induced
injury model involving the ligation of the main pancreatic duct, resulting in
severe injury and a two-fold increase in beta cell mass, the latter primarily
caused by increased beta cell cycling and neogenesis from a NGN3
(re)expressing embryonic-type endocrine progenitor. Discrepancies in the
literature stemming from this model, with regard to the increase of beta cell
cycling and the extent of NGN3+ progenitor cell differentiation towards
endocrine cells, emphasize the need for a standardized protocol. In this
thesis we provide a detailed protocol and a step-by-step video on how to
perform PDL surgery and what outcomes to expect. PDL is used to assess
the effect of inflammatory-mediated changes and cytokines and growth
factors on endocrine cell survival, proliferation and neoformation. The
JAK/STAT pathway, a prominent cytokine and growth factor responsive
pathway, is highly activated in multiple pancreatic celltypes in PDL and,
using pancreatic cell type-specific Stat3 knockout mice, we have shown that
it plays a role in protection of beta cells from excessive cycling and DNA
damage in PDL, sculpting some of the processes that occur in PDL and
regulating Ngn3 expression levels. To further evaluate the role of immune
cells in the processes observed following PDL, we have performed PDL
surgery on two immunodeficient mouse strains and observed a negative
effect on beta cell cycling but not on progenitor cell activation, suggesting a
crucial role for immune cells in mediating beta cell proliferation in the PDL
model.
Datum prijs31 jan 2017
Originele taalEnglish
Prijsuitreikende instantie
  • Vrije Universiteit Brussel
BegeleiderHenry Heimberg (Promotor), Mark Van De Casteele (Co-promotor), Leo van Grunsven (Jury), Ilse Rooman (Jury), Isabelle Manfroid (Jury), Raphael Scharfmann (Jury) & Luc Baeyens (Co-promotor)

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