Type 1 Diabetes Mellitus (T1DM) affects millions of children worldwide and is
increasing in prevalence. Exogenous insulin therapy is currently the mainstay of
treatment but is unable to prevent the chronic complications of this disease. Islet
transplantation is a successful, minimally-invasive, potentially curable alternative
treatment, which has restored physiological euglycaemia in up to 85% of recipients in
recent clinical trials. However, worldwide human donor islet shortages limit the wider
application of this treatment. Pluripotent cells may provide alternative islet sources to
overcome this shortage. The human spleen may be one such source and is an excellent
candidate tissue for further investigation.
The main aims of this thesis were to investigate whether the developing spleen could
differentiate into insulin-producing cells and to investigate the molecular mechanisms
behind this. Using an avian model of pancreatic development, I characterise normal
avian foregut expression of the splenic mesenchymal transcription factor Tlx-1
between E4-E11 of development and report an optimised in situ hybridisation
protocol for this. I use a chick-quail chimaera model of pancreatic organogenesis to
show that the developing avian spleen is able to differentiate into insulin-producing
cells in vitro through islet Mesenchyme-to-Epithelial Transition (iMET). 1 show
evidence that, when recombined with differentiating pancreatic epithelium, splenic
mesenchyme is reprogrammed to express the pancreatic islet genes Pdx-1 and Isl-1.
Tlx-1 is dramatically down-regulated during this process, indicating that this tissue is
reprogrammed from a splenic to pancreatic endocrine fate. Finally, an attempt to
augment splenic iMET is made through the addition of a Wnt agonist.
These findings, together with the recent discovery that the mature human spleen
contains Tlx-1 positive cells, may be a useful target for future bench-to-bedside
translation strategies for this work. Therefore, the spleen may be an ideal future tissue
source for islet transplantation to treat patients with T1DM.