Immune Evasive Stem Cell Islets

Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of insulin-secreting ß cells by the immune system (American Diabetes, A., Diabetes Care 32 Suppl 1:S62-67, 2009). It is characterized by fasting or post prandial elevated blood glucose levels and islet-associated autoantibodies (American Diabetes, A., Diabetes Care 32 Suppl 1:S62-67, 2009). While the administration of exogenous insulin remains the standard treatment for T1D patients, it does not restore pancreatic functionality and can result in hypoglycemia and long-term vascular complications (Fotino et al., Pharmacol Res 98:76-85, 2015; Latres et al., Cell Metab 29:545-563, 2019; Wang et al., Adv Sci (Weinh) 8, 2021). To date, the most effective approach to achieving normoglycemia and metabolic control in T1D patients is the transplantation of pancreatic islets (Hering et al., Diabetes Care 39:1230-1240, 2016). However, the shortage of cadaveric donors as well as the risk of immune rejection and the need for immunosuppressive therapies pose significant challenges. The production of differentiated ß cells from induced pluripotent stem cells (iPSC) represents a promising option to overcome these limitations. Indeed, iPSC are reprogrammed from adult somatic cells, providing a virtually unlimited source of cells for cell therapy (Millman et al., Nat Commun 7:11463, 2016). Moreover, the use of autologous patient-derived iPSC for ß cell transplantation does not elicit an immune response in the recipient (de Almeida et al., Nat Commun 5:3903, 2014; Sordi et al., Curr Diab Rep 17:68, 2017). However, the feasibility of a personalized approach, by which iPSC are generated and differentiated from individual T1D patients, is hampered by high costs and time-consuming procedures (Gornalusse et al., Nat Biotechnol 35:765-772, 2017; Sordi et al., Curr Diab Rep 17:68, 2017; Wang et al., Stem Cells Transl Med 4:1234-1245, 2015). Therefore, the identification of a strategy for ß cell replacement employing allogeneic iPSC or embryonic stem cells (ESC) and successfully escaping immune rejection is of the highest interest.