The objective of this pilot project is to evaluate the feasibility of the delivery of cytokine-modified stem cells in a rat model of renal transplantation. While renal transplantation is the ideal form of renal replacement in patients with stage 5 chronic kidney disease, the long-term success of renal transplants is limited due to acute and chronic rejection. The goals of this project are to provide anti-rejection protection to renal transplants by providing new functional renal cells to the transplant kidney. These cells will be derived from the recipient's mesenchymal stem cells (MSC) which are modified ex vivo with interleukin-10 (IL-10) and/or a reporter gene (eg. green flourescent protein) using adeno-associated viral vectors and seeded into the kidney at the time of transplantation. The studies in Aim I of this proposal will examine the feasibility of delivering modified MSC into the rat kidney in a model of renal transplantation. MSC will be isolated from male animals and the transplantation will be performed in females. The location of MSC in the kidney will be confirmed by the presence of the transgene and markers for the Y chromosome. Renal function and phenotyping of resident and infiltrating cells will be done to determine the component of cells derived from MSC. The experiments in Aim II will examine a similar approach in a rat model of renal transplantation using allografts (DA-Lewis) and isografts (Lewis-Lewis). It is expected that most of the MSC will infiltrate into the graft and differentiate into renal cells. The pre-existing IL-10 in MSC will prohibit MSC from differentiating into smooth muscle cells and immune/inflammatory cells. IL-10 secreted from MSC will inhibit the activation of endothelial cells and infiltration and activation of immune/inflammatory cells. This novel strategy will provide short and long-term benefits to the renal graft by decreasing ischemia-reperfusion injury, preventing immune rejection and providing functional renal cells, thereby prolonging graft survival.
| Deshane, Jessy; Chen, Sifeng; Caballero, Sergio et al. (2007) Stromal cell-derived factor 1 promotes angiogenesis via a heme oxygenase 1-dependent mechanism. J Exp Med 204:605-18 |
| Chen, B; Kapturczak, M H; Joseph, R et al. (2007) Adeno-associated viral vector-mediated interleukin-10 prolongs allograft survival in a rat kidney transplantation model. Am J Transplant 7:1112-20 |
| Chen, Sifeng; Wasserfall, Clive; Kapturczak, Matthias H et al. (2006) Freeze-thaw increases adeno-associated virus transduction of cells. Am J Physiol Cell Physiol 291:C386-92 |
