RESEARCH AREAS
Major Research Interests
Worldwide it is estimated that 387 million people have diabetes and this number is expected to increase 53% to 592 million by 2035. In the US, approximately 39 million Americans have diabetes, accounting for 9.3% of the population. Diabetes is the leading cause of kidney disease and non-traumatic amputations in adults and progressive disease often leads to severe eye, nerve and cardiovascular complications. In the US, healthcare costs related to treating diabetes and its complications cost hundreds of billions of dollars annually and continue to rise.
Despite continuing advances in insulin delivery technology and recombinant insulins, diabetes and its complications still claim the lives of millions of people largely because insulin fails to achieve perfect glycemic control. The burden of managing diabetes and the fear of low blood glucoses continue to exact a psychological toll on patients. On the other hand, beta cell replacement therapies including whole vascularized pancreas transplantation and isolated islet transplantation are able to fully restore normoglycemia, achieve insulin-independence and can delay end-organ complications. Indeed, pancreas transplantation by supplying additional functional beta cells is now highly successful and able to overcome an absolute and relative deficiency of beta cells in individuals with T1D and T2D, providing sufficient functional beta cells to eliminate the need for insulin long-term and improve patient survival. Islet transplantation from deceased donors can eliminate severe hypoglycemic events and may also improve patient survival in individuals with T1D. These studies provide proof of concept for a broadly applicable stem cell-derived islet cell replacement therapy.
However, these therapies suffer from several key limitations: the shortage of organs, inconsistent quality of donor organs, and the need for life-long immunosuppression to prevent allograft rejection and autoimmune recurrence. Thus, an ideal goal would be to provide insulin-producing tissue from an unlimited and replenishable supply of human pluripotent stem cells (hPSCs) and to engineer these cells to provide prolonged survival, or escape from immune recognition and destruction entirely, using currently available genome editing technologies. Moreover, as therapeutic hPSC derivatives have the potential for forming teratomas or undergoing malignant transformation, provision of an inducible suicide gene would offer protection from this occurrence.
Using these strategies, it may be possible to achieve an unlimited supply of consistently high quality “universal human beta cells” and overcome allo-and autoimmune mechanisms of destruction and protect from the development of rogue malignant cells in non-immunosuppressed patients, thereby providing a beta cell replacement therapy for millions of patients with insulin-dependent diabetes, including both Type 1 and Type 2 diabetes.
Clinical Outcomes Research in Pancreas and Islet Transplantation
In addition to stem cell research, our research enterprise conducts pancreas, islet and kidney transplant outcomes research using our UW Transplant Database, in collaboration with Department of Surgery statisticians (STARP) and the UW SMPH Department of Informatics and Information Technology.
NIH-funded Integrated Islet Distribution Program Islet Isolation Center
The UW Human Islet Core serves the greater islet research community by isolating islets from human deceased donor pancreata and distributing islets and tissues to investigators for non-clinical research. Peter Chlebeck, manager and lead scientist of the UW Human Islet Core, oversees the core activities.
Current Projects
The lab, under the co-leadership with Dr. Chamberlain, principal scientist and co-investigator, employs animal models and cutting-edge technology to understand the development of the beta cell fate from human pluripotent stem cells, improve transplantation outcomes into retrievable transplant sites through prevascularization, build a better home for stem cell-derived islets and cadaver islets by providing key matrix and vascular signals, and use genetic tools and humanized mouse models to understand and improve the immunogenicity of stem cell-derived islets.
Breakthrough T1D: Stem Cell-derived Islet Vascularized Extracellular Matrix Organoids for Enhanced Transplantation Success (Odorico PI)
Our hypothesis is that by adding ECM and endothelial cell (EC)/vascular network (VN) signals to islets and SCIs we will enhance their post-transplant engraftment and functional survival, and prevent “anoikis” thus leading to more robust and prolonged stable function in vivo. Our overarching goal is to construct 3D bioengineered islet organoids based on matrix hydrogel, endothelial cell vascular networks, and SCIs which we propose may overcome the biological, transplant site, and organ shortage limitations associated with currently available beta cell replacement strategies.
Falk Medical Research Trust Catalyst Award: A stem cell cure for diabetes enabled by novel immune evasion technology (Galipeau PI; Odorico CoI)
The goal of this project is to engineer hESCs with constitutive overexpression of a PD-L1-IDO transgene and to evaluate and characterize the SCI differentiation potential of the genetically engineered cells and then to evaluate their immunogenicity in humanized mice.
Office Vice Chancellor for Research: Multiomic Investigation of the Diabetic Islet Microenvironment and Islet Vascularized Matrix Organoids (Li PI; Odorico CoI)
The proposed work seeks to take a multiomic approach in analyzing human pancreatic islets and stem cell-derived islets with deep molecular coverage and high spatial resolution. The general hypothesis is that the paracrine and matrix-derived signaling within the human islet is exquisitely controlled, and gaining a better understanding of these events will help improve future islet products. The long-term research goal is to develop a clear understanding of the biomolecular composition of the human islet in order to develop new approaches to replace or preserve functional beta cells.