Objective
In this project, we will investigate the role of vascular signals in the functional maturation of stem cell-derived beta cells and explore ways to improve the outcomes of beta cell replacement therapy. By understanding how vascular cues contribute to the development and function of beta cells, we aim to advance cell-based treatments for individuals with type 1 diabetes.
Background Rationale
Blood vessels and endothelial cells play a crucial role in the maturation of beta cells during pancreas development. Stem cell-derived beta cells require transplantation and extended engraftment to achieve optimal function. We hypothesize that vascular-derived signals and endothelial cells provide essential nutrients and signals necessary for the functional maturity of beta cells. By leveraging these vascular signals and endothelial cells, we aim to enhance the maturation of stem cell-derived beta cells in the laboratory and improve the success of stem cell-derived islet transplantation in clinically relevant sites.
Description of Project
Type 1 diabetes is a global challenge without a definitive cure, calling for innovative treatment approaches. Human donor islet cell transplantation holds promise, but limited availability, impaired graft revascularization, and lifelong immunosuppression hinder its widespread use. An alternative solution lies in beta-like cells derived from induced pluripotent stem cells (iPSC-ß), which overcome donor scarcity and address immune rejection. However, these lab-grown iPSC-ß cells are functionally immature and need transplantation to acquire adult beta cell characteristics.
Our research investigates the impact of blood vessel-derived signals, specifically Vascular Endothelial Growth Factor-A (VEGF-A) and endothelial cell signaling, on the maturation of iPSC-ß cells. By comprehensive studies on cells cultured in the lab and animal models at islet engraftment sites, we aim to understand how vascular cues influence iPSC-ß cell maturation. We will uncover the underlying mechanisms that drive functional maturation when these cells are transplanted and use this knowledge to optimize the maturation process of iPSC-ß cells.
The findings of our study will significantly advance the field of islet cell transplantation, informing the development of improved strategies for iPSC-ß transplantation. This knowledge will pave the way for more effective cell-based therapies for type 1 diabetes. Unraveling the intricate interplay between VEGF-A, endothelial cells, and iPSC-ß cells will increase our understanding of beta cell biology and refine strategies for successful cell replacement therapy. Ultimately, our research has the potential to revolutionize curative approaches for type 1 diabetes, benefiting children and adults worldwide.
Anticipated Outcome
Through this project, we aim to address three key questions in the field of beta cell therapy for diabetes:
1. Are vascular signals required for the functional maturation of stem cell-derived beta cells after transplantation?
2. Can co-culturing stem cell-derived beta cells with endothelial cells improve their maturation in vitro?
3. By accelerating graft revascularization, can we enhance the engraftment success and metabolic outcome of stem cell-derived beta cell grafts at clinically relevant transplantation sites?
To answer these questions, the project is divided into three work packages:
• Work Package 1: Investigating whether stem cell-derived beta cell grafts require revascularization for functional maturation after transplantation under the kidney capsule.
• Work Package 2: Assessing if co-culturing stem cell-derived beta cells with endothelial cells improves their differentiation in the laboratory.
• Work Package 3: Determining if enhancing graft revascularization benefits the survival and function of stem cell-derived beta cell grafts in subcutaneous transplantation sites.
By successfully addressing these objectives, we expect to gain valuable insights into the role of vascular signals in beta cell maturation and develop strategies to enhance the success of stem cell-based therapies for type 1 diabetes.
Relevance to T1D
Type 1 diabetes requires a cure as current insulin treatment only manages glucose levels without addressing the underlying beta cell defect. Islet transplantation offers hope, but challenges such as donor shortage and graft dysfunction remain. Stem cell-derived beta cells hold promise, but achieving functional maturity in vitro is difficult.
In this project, we specifically focus on the role of vascular signals and endothelial cells in the maturation of stem cell-derived beta cells. Blood vessels and endothelial cells provide essential nutrients and signals necessary for the functional maturity of beta cells during pancreas development. By understanding and leveraging these vascular cues, we aim to enhance the in vitro maturation of stem cell-derived beta cells.
Moreover, we believe that the interplay between vascular signals and beta cells is crucial not only during development but also after transplantation. By investigating the impact of graft revascularization, we aim to optimize the engraftment process and improve the long-term metabolic outcomes of stem cell-derived beta cell grafts.
By unraveling the intricate relationship between vascular signals, endothelial cells, and beta cell maturation, this research aims to provide insights that can refine strategies for successful beta cell replacement therapy. Ultimately, our goal is to contribute to developing novel and effective treatments that can cure type 1 diabetes.