Description:

Presenter: Joseph Uzarski, MD

The growing shortage of donor kidneys suitable for transplantation has resulted in extensive waiting list periods for patients suffering from end-stage renal disease. Conceptually, the future ability to create patient-specific, bioengineered kidney grafts on demand would combat the severe deficiency in donor organ availability, improving the quality of life and survival of patients in desperate need of transplantation. This would be accomplished by combining renal extracellular matrix scaffolds with renal parenchymal cells that have been derived from the patient, allowing us to create tailorable grafts that would not suffer from immunological rejection, potentially eliminating the need for patient immunosuppression. While working toward this long-term goal, we are currently using decellularized rodent kidneys as model three-dimensional extracellular matrices for developing strategies to re-create a functional nephron ex vivo. This seminar will focus on three different phases on the road to our long-term goal of building a kidney graft suitable for transplantation: 1) optimizing the decellularization process to create acellular, yet biologically active extracellular matrices from Sprague Dawley rat kidneys, 2) using custom-developed bioreactor systems to evaluate multiple cell seeding methods for effective repopulation of these scaffolds using various parenchymal/stromal cell sources, and 3) characterizing the ability of epithelial cells to mature to form patent tubular structures within these three-dimensional scaffolds during perfusion culture. Our results show that our decellularization process results in the creation of bioactive, structurally intact whole-kidney extracellular matrices that support growth of proximal and distal tubule-derived epithelial cells, microvascular endothelial cells, and stromal fibroblasts, which can be used to repopulate the various tubular, vascular, and interstitial niches, respectively. We further show that renal cortical tubular epithelial cells form mature, polarized tubular structures over one week of perfusion culture within our bioreactor system. This work represents progress toward the long-term vision of building a bioengineered kidney graft for clinical transplantation.