Objective
The objective of this research is to produce islets from human pluripotent stem cells that have increased survival after transplantation for use in cell replacement therapy. We will study the influence of gene expression within these cells on survival and phenotype of stem cell-derived islets.
Background Rationale
As Type 1 diabetes is caused by the destruction of insulin-producing pancreatic islets, patients could potentially be cured by transplantation of exogenous islets. However, the supply of donor cells is very limited and of variable quality, making this approach infeasible to help the millions of patients that could benefit. We have developed methods for making functional islets from human pluripotent stem cells in vitro. These stem cell-derived islets (SC-islets) have many of the features of adult islets and can alleviate diabetes in mouse models. SC-islets are a renewable, virtually limitless cell source that overcomes current shortages of donor cells. However, currently most cells die shortly after transplantation for the treatment of Type 1 diabetes. We hypothesize that specific genetic edits can improve the survival of SC-islets to maximize their functional efficacy in vivo.
Description of Project
The rapid rise in the occurrence of Type 1 diabetes has garnered much attention in the development of technologies to better study and treat this disease. There is no cure for Type 1 diabetes, and current diabetic treatments are insufficient in controlling diabetes in many patients. Patients could potentially be cured by transplantation of exogenous islets. We have developed approaches to produce a virtually unlimited number of functional islets from human pluripotent stem cells in the laboratory. Here we propose to modify these cells to increase their utility in diabetes cell replacement therapy by increasing their survival after transplantation.
Anticipated Outcome
The expected outcome of this contribution is a detailed understanding of the genetic regulation of SC-islet survival after transplantation. The outcome of this proposal will have a positive impact by filling gaps in our understanding of what controls SC-islet survival in diabetes cell replacement therapy. Successful completion of our studies will inform future strategies to improve SC-islet genetic engineering for diabetes cell replacement therapy.
Relevance to T1D
This proposal is highly relevant to Type 1 diabetes by increasing our understanding of how to deliver stem cell-derived islets into patients that maximize their survival, thereby increasing the likelihood the recipient will no longer require exogenous insulin injections. The use of stem cells with our differentiation approach provides a potentially unlimited number of stem cell-derived insulin-producing islets for applications that are very important to Type 1 diabetic patients. The cellular products I generate could be transplanted into Type 1 diabetic patients, with these exogenous cells replacing the function lost in the endogenous islets, thus controlling patient blood glucose without insulin injections.