Abstract
SummaryThe scarcity of donors and need for immunosuppression limit pancreatic islet transplantation to a few patients with labile type 1 diabetes. Transplantation of encapsulated stem cell-derived islets (SC islets) might extend the applicability of islet transplantation to a larger cohort of patients. Transplantation of conformal-coated islets into a confined well-vascularized site allows long-term diabetes reversal in fully MHC-mismatched diabetic mice without immunosuppression. Here, we demonstrated that human SC islets reaggregated from cryopreserved cells display glucose-stimulated insulin secretion in vitro. Importantly, we showed that conformally coated SC islets displayed comparable in vitro function with unencapsulated SC islets, with conformal coating permitting physiological insulin secretion. Transplantation of SC islets into the gonadal fat pad of diabetic NOD-scid mice revealed that both unencapsulated and conformal-coated SC islets could reverse diabetes and maintain human-level euglycemia for more than 80 days. Overall, these results provide support for further evaluation of safety and efficacy of conformal-coated SC islets in larger species.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of insulin-secreting b cells in the pancreas, leading to impaired blood glucose regulation (Atkinson et al, 2014)
The fraction of mature b cells (NKX6.1+ C-peptide+) in SC islets was found to increase during S6 reaggregation from 12.7% to 36.1% and from 19.2% to 33.8% compared with end-of-stage-5 (S5) (Figure 1E)
Characterization of SC islet functionality during reaggregation revealed that dithizone (DTZ) staining was weaker in S6d7 cells (d6 reaggregation) (Figure 1F), which corresponded to lower glucose-stimulated insulin secretion (GSIS) functionality compared with S6d11 (Figure 1G), GSIS indexes and deltas were comparable (Figure 1H)
Summary
Type 1 diabetes (T1D) is an autoimmune disease involving T cell-mediated destruction of insulin-secreting b cells in the pancreas, leading to impaired blood glucose regulation (Atkinson et al, 2014). Despite sustained scientific progress in the field, most patients still rely on exogenous insulin to manage T1D (Redondo et al, 2018; Skyler, 2018). Transplantation of insulin-secreting cells is indicated in individuals with labile T1D to replenish the insulin source and restore glucose homeostasis (Dean et al, 2017; Schuetz and Markmann, 2016; Shapiro et al, 2017). The islet transplantation field has grown tremendously in the past decades (Hering et al, 2016). Two of the major limiting factors of pancreatic islet transplantation are the scarcity of donors and the need for life-long immunosuppression to prevent islet rejection and recurrence of autoimmunity (Stegall et al, 1996)
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