Background: Islet transplantation is an established treatment for type 1 diabetes mellitus. However, many recipients do not achieve independence from exogenous insulin since up to 5070% of islets are lost post-transplant. An important factor determining transplant success is graft vascularisation. The epidermal growth factor receptor (EGFR) is a key pro-survival and proliferation factor. Here, we investigate for the first time if EGFR overexpression in pancreatic islets improves engraftment in an in vivo mouse model.
Methods: We generated adenovirus encoding human EGFR alongside a GFP reporter in order to overexpress this protein in primary tissue. Following successful infection (as assessed by GFP expression), control (empty vector) or EGFR-infected islets were transplanted into the anterior chambers of the eyes of syngeneic mice (n=12 eyes randomly receiving either EGFR or control islets). Islet volume and blood vessel density/branching were assessed longitudinally over 30 days using confocal microscopy. To assess implantation, beta cell identity and function, expression of angiogenesis (eg VEGF), beta-cell enriched (eg Pdx1 and MafA) and beta-cell disallowed (eg Acot7 and LdhA) genes was determined by qPCR from identically infected islet groups (in vitro).
Results: Blood vessel density increased significantly over 30 days for both groups of islets (P<0.05), with EGFR-overexpressing islets demonstrating greater density compared to control islets at 30 days. qPCR results showed that EGFR-overexpressing islets had increased gene expression of angiogenic factors. Furthermore, consistent with preserved beta cell identity, beta-cell enriched factors were upregulated compared to control islets, while beta-cell disallowed genes were further repressed.
Conclusion: This is the first study to demonstrate that EGFR overexpression can promote the vascularisation of transplanted pancreatic islets in vivo. The transcriptional profiling of these islets also suggests an improved potential for beta-cell regenerative capacity and function. Further studies are underway to fully investigate the therapeutic potential of this intervention.