By 2030, diabetes is expected to be the third leading cause of death worldwide. While beta cell (an insulin producing pancreatic cell) therapy has shown success in animal studies, growing evidence suggests that beta cells alone do not offer a long-term solution. Both type 1 (usually diagnosed in childhood) and type 2 (usually diagnosed in adults) diabetes diseases are affected by two hormones: insulin, whose role is to reduce glucose in the blood stream, and glucagon (produced by alpha cells), whose role is to increase glucose in the blood stream. Interactions between alpha and beta cells are thought to be essential to maintaining blood glucose stability. In fact, alpha cell dysfunction is a major cause of excessive glucose production and insulin resistance in diabetic patients. Furthermore, two other cell types (delta cells and pancreatic polypeptide cells (PP)) regulate both insulin and glucagon secretion. Thus, engineered whole islets (insulin producing tissues) should entail all cell types: alpha, bet, delta, and PP cells, but such a diabetes tissue model is currently unavailable. This team has pioneered the generation of islet organoids (clusters of islets) from induced pluripotent stem cells (iPSCs = stem cells that can become any cell type). A particular form of collagen, referred to as ColV, was found to enable self-assembly of the iPSCs into islets that contain of all the cell types and could generate glucose-responsive secretion of insulin and glucagon. The goal of this project is to uncover and intensify the ColV signal pathways required for islet development and maturation. Project outcomes are expected to lead to the fabrication of functional islets from iPSCs, thereby transforming the field by offering an endless supply of islets for diabetes therapy, drug testing and diabetes related research. The project will extend the team's efforts to establish a strong research and educationally integrated program and to bring science and engineering to the public and younger generations, especially to those from underrepresented groups. The research will provide opportunities to train undergraduate and graduate students, including minorities, and reach out to K12 students to encourage their pursuits in science and engineering at the early stage of their careers.
The overarching goal of this project is to generate whole islets from iPSCs to address the need for an in vitro diabetes tissue model that entails pancreatic cells known to be involved in maintaining blood glucose homeostasis: beta, alpha, delta and pancreatic polypeptide (PP) cells. The project builds on the team's preliminary studies that revealed that cell clusters self-assemble into functional islet organoids after exposing iPSCs to a tissue-specific ECM (extracellular matrix) niche consisting of the pancreatic ECM protein Collagen V (ColV) in Matrigel. These findings led to the project's central hypothesis that pancreatic ECM proteins, such as ColV, are critical to islet organogenesis and morphogenesis during iPSC pancreatic differentiation. To test this hypothesis, the project plans to systematically interrogate ColV for its instructive role in assembling a human islet architecture of iPSC derived indocrine cell clusters. The synergistic ColV signal transduction pathways involved in islet development and maturation will be unveiled. The Research Plan is organized under two objectives. The FIRST Objective is to discover ColV's organogenesis signal for islet development and maturation from iPSCs. Studies will be designed to examine whether islet maturation can be further elevated by exposing iPSCs to a higher concentration of ColV and to determine if the ColV signal is differentiation stage-specific and if so, to determine which stage is the most critical for exporting ColV signals to induce islet organogenesis. Cellularity and maturity will be characterized at genotype and phenotype levels to evaluate their quality and function for use as a tissue model for diabetes study or as human islet replacement for diabetes treatment. The SECOND Objective is to decipher the ColV signaling pathways involved in islet development and maturation considering both extrinsic and intrinsic factors. Unlocking the underlying mechanisms of the ColV signal will help design a better islet development system to enhance or suppress key molecules engaged in transduction pathways critical to islet organogenesis, morphogenesis, and maturation. The focus will be on elucidating ColV induced signaling pathways and their role in regulating and controlling islet organogenesis, morphogenesis, and maturation. Cellular receptors involved in ColV-cell interactions will be identified and intracellular signaling proteins and effector proteins for ColV signaling will be pinpointed.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
