Our goal is to use stem cells and cutting-edge technologies for the study and treatment of diabetes
Generating Stem Cell-Derived β Cells
We use embryonic and induced human pluripotent stem cells to model β cell development and differentiation. We have successfully generated a new state-of-the-art protocol for the in vitro generation of glucose-responsive SC-β cells secreting high amounts of insulin with secretion dynamics approaching that of primary islets, presenting robust first and second phase insulin secretion curves capable of rapidly reversing diabetes in mouse models. Using our SC-β cell differentiation strategies and expertise with bulk and single-cell RNA sequencing technologies we have identified and are investigating novel signaling pathways regulating β cell differentiation and functional maturation.
Genetic Modification of Islets
Genetic engineering approaches offer new opportunities to study cellular differentiations in pancreatic development, as well as designing cells to carry additional features to enhance islet performance. Specifically, we are exploring ways to enhance the functionality of SC-islets by addressing the maturation properties and stress induced signals found in adult human islets and T2D islets respectively. We are interested in using modern CRISPR technologies, such as CRISPR/Cas9 and/or CRISPR i/a as platforms to genetically modify the cells.
Bioengineering Islet Tissue Microenvironment
To further enhance differentiation efficiency to a β cell fate, we have recently utilized tissue engineering approaches to augment microenvironmental cues that influence endodermal cell fate decisions. In order to assess the effects of these cell-biomaterial interactions, we have used single cell RNA sequencing and bioinformatics tools to analyze cell populations generated in response to stimuli from the microenvironment. Exploring the genetic profiles of these populations has enabled us to identify key signaling components and biological pathways important for endocrine induction, β cell specification, and β cell maturation. We have developed methodologies to gain precision control of these pathways which has allowed for significant improvements in β cell function.
Modeling Diabetes Using Patient-Derived Cells
Generation of β cells from diabetic patient-derived iPS cells offers a unique window into the study of disease progression and development. We use SC-β cells to study multiple types of diabetes including Type 1, Type 2, and monogenic forms. We can characterize patient-derived SC-β cells through Seahorse to evaluate mitochondrial respiration, conventional dynamic and static functional assays, transplantation to treat diabetes in animal models, and next generation sequencing. This platform allows for personalized therapy through drug screening to identify patient-specific therapeutic targets and autologous cell therapy using a patients’ own cells. In addition, specifically for monogenic forms of diabetes, we can utilize CRISPR/Cas9 to correct diabetes causing mutations and generate functional SC-β cells for autologous cell replacement therapy.