Kidney failure is a critical health problem in the United States and it reflects the consequences of failed nephron repair and progressive fibrosis. Two promising strategies to treat kidney failure include regeneration of functional nephrons in vivo, and engineering of transplantable nephrons in vitro. We have identified two critical adult kidney progenitor populations with strong potential to play important roles in each strategy. Within the tubule, we have previously shown that dedifferentiated proximal tubule cells are responsible for repairing proximal tubule by proliferative expansion. We have now generated a novel approach to easily isolate a pure population of these dedifferentiated epithelial progenitors, and we will characterize, culture and define the functional properties of these critical cells. In addition, we have recently identified a kidney resident mesenchymal stem cell population defined by expression of Gli1 that represents the major myofibroblast precursor population in fibrotic disease. These cells have vascular stabilizing properties and are capable of differentiating into both pericytes and vascular smooth muscle cells. We will further characterize the function of these cells both in vitro and in vivo, and coculture them with endothelial cells and epithelial cels to model the kidney tubulointerstitium in vitro. Together, the proposed experiments will not only define novel regenerative strategies for kidney failure, but will also validate two critical adult progenitor cell populations that will be useful for a variety of regenerative approaches to treat kidney failure.
Failure of kidney repair leads to kidney fibrosis which is the leading cause of kidney failure worldwide, representing an enormous health burden. The ability to enhance endogenous repair, or replace function once lost with a bio-engineered kidney, would address this unmet medical need. We have described two progenitor cell populations within the adult kidney: dedifferentiated proximal tubule cells and a novel stromal progenitor cell type in the interstitium. We hypothesize that these progenitors can be manipulated and isolated to enhance nephron repair and slow disease progression, and to engineer kidney tissue within a dish. The experiments in this application are designed to better define understand the capacity of these cells to repair nephrons and to establish a proof of principle that they can be used to help engineer self-organizing nephrons ex-vivo.
