One of the major barriers to successful islet transplantation is the limitation of available islets. Increasing the supply of islets using therapeutic gene delivery can theoretically be accomplished in several ways including creating islet surrogates by directing cell differentiation of various progenitors, by genetic engineering of glucose-responsive cells to create functional beta cell surrogates or by strategies designed to protect islets after transplantation that could even allow successful xenotransplantation. Common to all these strategies is the requirement to transplant islets, differentiated stem cells or engineered islet surrogates. The underlying premise of our ongoing research in tissue engineering for islet transplantation is that the ability to control the implantation site and to enhance the revascularization of transplanted cells will create a platform to advance the field regardless of the specific strategy taken to provide the insulin-producing cells. Specifically, we have demonstrated that addition of endothelial progenitors to a novel three-dimensional collagen template technology we have developed for islet transplantation, significantly increases angiogenesis, a critical step in successful engraftment of a cell transplant. We now propose to use lentiviral vectors for therapeutic gene delivery to the endothelial progenitors. Our hypothesis is that as they revascularize the islet transplants they will produce antiinflammatory, antirejection and/or proangiogenic proteins locally within the transplant site and eventually deliver these directly via the vascular supply of the islet grafts. Moreover, demonstrating a proof of concept for delivering soluble factors in this manner will open the way to delivering other molecules such as growth, proliferative, differentiative and anti-apoptotic factors as required to complement other strategies for islet engineering, fulfilling the promise of a platform technology. ? ? Our strategy of using endothelial progenitors as the vehicles for gene delivery has two additional advantages. First, it does not require any manipulation of the islets for therapeutic gene delivery and, thus, does not complicate the already complex process of islet isolation, purification and culture. Second, we propose that the endothelial progenitors be derived from the host so that the islets or islet surrogates are revascularized with host vessels providing therapeutic molecules. This has obvious immunological advantages but also allows us to take advantage of our ability to create stable endothelial monolayers for gene transduction and do all the required safety testing long before the transplant, something that will be difficult in strategies where islets are the direct targets.
| Cherqui, Stephanie; Kingdon, Kenneth M; Thorpe, Camille et al. (2007) Lentiviral gene delivery of vMIP-II to transplanted endothelial cells and endothelial progenitors is proangiogenic in vivo. Mol Ther 15:1264-72 |
| Cherqui, Stephanie; Kurian, Sunil M; Schussler, Olivier et al. (2006) Isolation and angiogenesis by endothelial progenitors in the fetal liver. Stem Cells 24:44-54 |
