Pancreatic islets consist of different endocrine cell types, named α-, β-, δ- and γ-cells, which produce glucagon, insulin, somatostatin and pancreatic peptide (PPY) hormones, respectively. These cells receive external and local cues in order to ensure blood glucose homeostasis. β-cells release insulin in response to elevated blood sugar levels after meals, to promote glucose uptake by peripheral tissues. Conversely, glucagon released by α-cells mobilizes glucose from the liver during low blood glucose conditions such as fasting.
In type 1 diabetes (T1D), β-cells are massively destroyed by an aberrant autoimmune attack. Consequently, T1D patients rely on daily insulin injections to cope with hyperglycemia and to prevent the severe associated complications. However, exogenous insulin administration does not faithfully recapitulate the precise and regulated insulin release by β-cells. T1D patients who fail to control their blood glucose at near normal level with insulin therapy are eligible for islet cell transplantation. Due to the limited availability of human islets from cadaveric donors, there is a need to find alternative sources of β-cells for cell replacement purposes. Current efforts focus on differentiating β-like cells from human embryonic (ES) or induced pluripotent stem cells.
The present thesis will focus on the potential of exploiting the plasticity of adult non-β islet cells (i.e α-, δ- and γ-cells) to generate functional glucose-regulated insulin-secreting cells by cell reprogramming. The included publications provide a retrospective view of the major observations from our laboratory concerning the regenerative capacity of the adult pancreas, particularly the plasticity of adult islet cells in mice. The first evidence of α-cell plasticity toward insulin production in diabetic mice, the characterization of the underlying mechanism and how this knowledge can be used to promote the conversion of human islet cells are discussed here.
Our findings reveal the unexpected potential of adult islet cells from both mice and human to be reprogrammed into glucose-responsive insulin-secreting cells. Further work is required to enhance the functionality of these reprogrammed cells for future T1D therapies.
