MICA: Harnessing human Schwann cell-pancreatic progenitor cell interactions to optimise cell replacement therapy for type 1 diabetes

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Diabetes currently affects nearly half a billion people worldwide, approximately 10% of whom have type 1 diabetes (T1D). T1D occurs when the specialised insulin producing beta-cells in the pancreas are destroyed by the immune system. These cells can be replaced in people with T1D to improve blood glucose regulation, but this treatment is limited because there are insufficient beta-cell donors. One potential strategy for overcoming this problem is to generate large numbers of human beta-cells for transplantation from human stem cell populations, which are readily available. However, current methods for producing beta-cells from human stem cells rely on information obtained from studies using developing mouse pancreas: these methods are inefficient and do not produce functional human beta-cells. This is mainly due to the differences in the signalling pathways regulating development of mouse and human pancreas. Although the in vitro approach of generating hiPSC-derived beta cells is aimed at mimicking the complex microenvironment in which beta cells develop, our knowledge of the contribution of the pancreatic microenvironment to beta-cell development remains incomplete. I have therefore systematically profiled the developing human pancreas microenvironment using novel technologies to reveal that Schwann cells are spatially co-located with endocrine progenitors and they may contribute to beta-cell specification and maturation. This Fellowship project will therefore harness the human Schwann cell-endocrine progenitor interactions to improve differentiation of hIPSC-derived pancreatic progenitors to beta-like cells and assess the function of those cells in vitro and in vivo, using a mouse model of type 1 diabetes. The knowledge obtained from this project will, in the longer term, be used to optimise cell replacement therapy for type 1 diabetes treatment in humans.