The overall goal of this proposal is to bioengineer pancreatic beta cell-containing implants for treatment of diabetes. A major obstacle to successful transplantation of human islets is their decreased survival caused by damage during their collection and lack of adequate revascularization post-transplant. Conditions have been developed that support the survival and function of human islets in vivo in SCID (severe combined immunodeficient) mice. We previously established conditions for formation of a human microvascular bed derived from human endothelial cells (EC) that are cast in collagen/fibronectin gels and then implanted into SCID mice. Casting the islets together with EC effectively revascularize the islets. Indeed, our pilot data indicate that these human islet-EC microorganisms secrete human insulin into the peripheral blood of mice for periods of at least 4 months and demonstrate responsiveness to glucose in glucose tolerance tests.
The first aim of this project is to characterize the structure/function properties of this microorganism, including the microvessel structure and the stability of the microvessels with time. Since the secretion of human insulin improves over time, we will test for proliferation of beta cells and also examine whether these microorganism can cure chemically-induced diabetes in mice. In the second aim, we will test the function of the revascularized islets when they are exposed to alloreactive human cells. Bcl-2 overexpression renders human EC resistant to allorejection. We hypothesize that the islets revascularized with Bcl-2-transduced EC will not be affected by the allogeneic human lymphocytes. For clinical use it will be necessary to develop a larger microorgan implant and optimize conditions for both survivals of beta cell function and revascularization.
The third aim will utilize various synthetic molecular scaffolds to increase the size and function. Finally, the use of microspheres will be optimized for the delivery of factors that will promote beta cell survival and function. This model will have significant implications for improving post-transplant survival of human islets.
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