Objective
Allogeneic cell therapy is emerging as a cure for Type 1 Diabetes. Due to paucity of available islet donors, islet transplantation is unable to deliver islets in sufficient quantities for the vast number of patients with diabetes. Human pluripotent stem cells h(PSC)-derived islets are a promising source for cell replacement, as these cells could serve as an unlimited supply of β-cells for all patients with diabetes. Our goal is to enhance the metabolic maturity of hPSC-derived islet organoids augmented by novel integrated modeling and pharmacological approaches to ultimately improve hPSC islet function both in vitro and after transplant, ultimately leading to efficient engraftment and function that restores normoglycemia in diabetes. In the future, this strategy can be paired with existing immunosuppressive therapies, or with emerging tolerance therapies to prevent rejection. We have published on localized cytokine delivery that can attenuate inflammatory responses that facilitate engraftment as well as FasL modification to create an immune-privileged site, which could be combined with these results in future studies.
Background Rationale
The contribution of metabolic flux through the mitochondria to GSIS is a well-appreciated aspect of β-cell function. In addition to the critical roles of mitochondria to support insulin release through oxidative phosphorylation (OXPHOS), numerous other metabolic processes are vital to meet the energy demands of GSIS. As such, limitations in mitochondrial function or metabolism lead to impaired glucose stimulated insulin secretion. Indeed, recent reports demonstrate that hPSC-derived β-cells lack optimal mitochondrial function both in vitro and in vivo, which may decrease β-cell function and survival in the challenging transplant environment and limit their long term ability to maintain glycemic control in patients. Despite the connections between mitochondrial health and insulin release, the mechanisms underlying the limitations in mitochondrial function in hPSC-derived β-cells are unclear.
Mathematical modeling of GSIS in mature β-cells has been successfully employed to understand how perturbations in the secretory pathway leads to the development of diabetes in humans. Indeed, mathematical models iteratively improved by rigorous experimental data, such as the integrated oscillator model, have been essential to arrive at a deeper understanding of metabolism in the control of insulin release. Similar modeling is indispensable to understand the regulation of β-cell mass with age and stress. Moreover, computational models have been applied to understand hPSC differentiation. Despite the rapid expansion in the study of hPSC-derived islets, computational models driven by transcriptomic, metabolic, and functional data have yet to be applied to determine if they could be applied to guide an improved developmental trajectory towards more metabolically mature and functional islets.
Description of Project
Type 1 diabetes (T1D) affects an estimated 1.25 million people in the US, and the most common treatment is life-long exogenous insulin. Although insulin therapy has been successful, hypoglycemic events and vascular complications persist. Intraportal allogeneic islet transplantation has had successful clinical results. Due to paucity of available islet donors, islet transplantation is unable to deliver islets in sufficient quantities for the vast number of patients with diabetes. Human pluripotent stem cells h(PSC)-derived islets are a promising source for cell replacement, as these cells could serve as an unlimited supply of β-cells for all patients with diabetes. Differentiation of hPSC towards the β-cell fate requires a complex ~1 month, 6 stage protocol, moving from pluripotent cells to insulin+ cells. However, these protocols produce insulin+ β-cells at a relatively low efficiency that are not fully functional in vitro, have poor glucose-stimulated insulin secretion (GSIS), and do not acquire the features of fully mature β-cells. Our goal is to enhance the metabolic maturity of hPSC-derived islets augmented by novel integrated modeling and pharmacological approaches to ultimately improve hPSC islet function both in vitro and after transplant, ultimately leading to efficient engraftment and function that restores normoglycemia in diabetes. In the future, this strategy can be paired with existing immunosuppressive therapies, or with emerging tolerance therapies to prevent rejection.
Anticipated Outcome
These experiments will lead to higher functioning hPSC-derived islets with more regulated glucose stimulated insulin secretion and greater therapeutic impact for applications in T1D treatment. Additionally, identifying metabolic network changes that impact ꞵ-cell metabolic competence could be leveraged to enhance ꞵ-cell function, as the link between metabolism and differentiation has been well established in other models. These tools may also lead to improved cell manufacturing or identify markers that can be used for validation of manufacturing efficacy.
Relevance to T1D
Type 1 diabetes (T1D) affects an estimated 1.25 million people in the US, and the most common treatment is life-long exogenous insulin. Although insulin therapy has been successful, hypoglycemic events and vascular complications persist. Intraportal allogeneic islet transplantation has had successful clinical results, yet is limited by a shortage of donor islets, for which human pluripotent stem cells represent an unlimited source of functional β-cells. Our goal is to enhance the metabolic maturity of hPSC-derived islet organoids augmented by novel integrated modeling and pharmacological approaches to ultimately improve hPSC islet function both in vitro and after transplant, ultimately leading to efficient engraftment and function that restores normoglycemia in diabetes.