We have shown that rat and mouse metanephric mesenchyme (MM) and ureteric bud (UB) cells undergo reciprocal induction to form differentiated tubular epithelium and undergo vasculogenesis forming capillary-like structures in 3-dimensional culture. Because these kidney progenitor cell lines retain differentiation potential, they have enormous potential in state-of-the art areas of research including cell-based therapy, stem cell biology, tissue engineering, and other burgeoning fields in regenerative medicine. This proposal is designed to establish the efficacy of the progenitor cell lines in cell-based therapy to accelerate repair and recovery during acute kidney injury. Information derived from these studies will be used to further commercialize the cells and optimize distribution to the scientific community, fostering investigation in nephrogenesis and regenerative medicine. The following aims are proposed:
Aim 1. To define differentiation potential of kidney embryonic progenitor cells in cell-based therapy in acute kidney injury. The therapeutic potential of rodent MM, UB, and glomerular progenitor (GP) cells derived from the nephrogenic zone of the developing kidney will be critically evaluated in cell-based therapy to repair injured structures during acute kidney injury. The ability of the cells to repair tubular and vascular structures via paracrine mechanisms and/or by cell integration will be explored. Three established experimental models of acute kidney injury are selected for proof of concept testing: 1) Ischemia/reperfusion;2) bromoethylamine hydrobromide (BEA)-induced papillary injury;and 3) Thy- 1-induced mesangioproliferative glomerulonephritis. The models were chosen for their selective damage and drop-out of specialized cell types unique for each disease targeting potential of the progenitor cells to repair proximal tubular cells, the collecting duct, or glomerular mesangial and endothelial cells. Efficacy of cell replacement therapy will be determined by histopathological and functional assessment.
Aim 2 will examine the efficacy of secretory products derived from each kidney progenitor cell line as therapeutic modalities to treat acute kidney injury.
Aim 2 is designed to examine the efficacy of conditioned medium derived from each of the embryonic progenitor cell lines as therapeutic test agents to accelerate recovery of intrinsic cellular targets in the three models outlined in Aim 1. The active components of the conditioned media in successful experiments will be determined during Phase II. Information derived during the course of this Phase I grant will be used to transition into a subsequent Phase II grant in which corresponding progenitor cells will be isolated from baboon embryonic kidney and used to treat acute kidney injury in non-human primates as a prototype therapy for human disease. Probetex in cooperation with the UTHSCSA and the Southwest National Primate Research Center (SNPRC) at the Texas Biomedical Research Institute (TBRI) has a unique opportunity to procure and test baboon kidney progenitor cells in acute kidney injury in non-human primate models.
Renal stem-cell technologies in treatment of renal disease are in their infancy. This application investigates the efficacy of metanephric mesenchymal, ureteric bud and glomerular progenitor embryonic kidney cell lines in cell-based therapy to treat acute kidney injury in rats. Rat kidney progenitor cell lines will be used to explore roles for cell integration and/or paracrine mechanisms in renal repair processes after injury. A commercial source for kidney progenitor cell lines for investigation in regenerative medicine is not available Determination of efficacy of these cells to ameliorate kidney disease will foster further research in this important area of regenerative medicine.