Objective
It is estimated that 50 to 80% of transplanted beta cells die within a week after transplant because of limited blood supply. This severely limits the efficacy of beta cell replacement therapy. Our proposed research aims to address challenge so that majority of transplanted beta cells survive and function.
Background Rationale
The reason most transplanted beta cells die is because they have limited blood supply in the new transplant site. In the pancreatic islets, every beta cells are in contact with capillaries that provide oxygen and nutrients to the beta cells and transport out wastes. This rich blood supply also allows beta cells to efficiently sense changes in blood glucose and release insulin into the blood. During islet transplantation, the first step of isolating the islets from donors severs the blood vessels connected to beta cells. The isolated islet clusters are then placed into a new site in the recipients. Because the blood vessels in the islets are too numerous and too small, the islet clusters are sutured to the blood vessels of the recipient, resulting in a sudden loss of blood supply. Stem cell-derived beta cells are cultured in nutrient-rich media with plenty of oxygen. They similarly suffer from the sudden decrease of oxygen and nutrients after transplant. We believe we can improve the survival of islets and stem cell derived beta cells by preparing them for the change of blood supply. Moreover, we can also prepare the tissue the cells will be transplanted into to grow more blood vessels so that they can reach to the transplanted cells faster. We will test this strategy using human islets and stem cell derived beta cells. We will transplant them into the space under the skin in mice. We will use drugs to treat the graft cells and the skin tissue to create an artificial low oxygen state without depriving them of the oxygen. This treatment will provide the cells time to adjust and allow the blood vessel to grow in the skin. We will measure graft survival and function to determine the efficacy of this strategy.
Description of Project
Poor beta cell survival after transplant is a major barrier to realizing the full potential of the therapy. Unlike most transplanted organs, islets are not surgically connected to the vasculature of the recipient during transplant but rely on new blood vessel formation to regain blood supply. Thus, for days to weeks, transplanted islets have limited access to oxygen and nutrients. It has been estimated that 50 to 90% of transplanted beta cells die due to ischemic injury. The investigation proposed in this application aims to address this critical barrier of beta cell replacement therapy to improve the outcomes of the therapy. The major reason for the massive cell death after transplant is the sudden and severe loss of blood supply similar to heart attacks and ischemic strokes. Most tissue can adapt to a gradual reduction in blood supply by reducing their metabolism and promoting new vessel growth. Our approach is to tap into the this natural adaptation program. We will treat beta cells with a drug to initiate adaptation to low oxygen prior to transplant. We will also pretreat the skin tissue with the same drug to increase blood vessel growth before transplanting beta cells into the tissue. We will test if combining these two approaches would allow most transplanted beta cells to survive and function in mouse models.
Anticipated Outcome
At the conclusion of this study, we will learn how effective this strategy is in improving beta cell survival and function after transplant in mouse models. Strong efficacy data, if generated, would provide justification for clinical translation.
Relevance to T1D
This project aims to improve the outcome of beta cell replacement therapy, thus is directly relevant to type 1 diabetes therapy, particularly for those with long-standing diabetes.