Increasing Ductal Cell Plasticity to Facilitate Beta Cell Reprogramming
People who have Type I diabetes lose their insulin cells due to the body destroying them. The field of regenerative medicine has been investigating how to change non-insulin cells into insulin cells as an alternative to islet donors for people who need islet transplantation. The challenge in this approach is that it is not simple to change cellular identities. Cells use DNA methylation, which is the addition of a small carbon group onto DNA, to “lock-in” cellular identity. This project seeks to use the ductal cells of the pancreas to make new insulin cells. We think that DNA methylation keeps the specialized ductal cells different from the specialized insulin cells. We hypothesize that if we delete the factor that maintains DNA methylation in cells, DNMT1, ductal cells will be more able to change into an insulin cell. We will explore this in both mouse models and human ductal cells. This project is a novel take on an idea that has been challenging the field for a long time. We believe that DNA methylation prevents ductal cells from changing identity to become a functional beta cell. We want to delete the factor that maintains DNA methylation, DNMT1, to investigate the role of DNA methylation in maintaining ductal cell identity. There are FDA approved small molecules that can inhibit DNMT1. If we are successful, this research could potentially be translated into a new method to differentiate insulin cells from ductal cells.