Despite significant advances in our understanding of the pathogenesis of ischemic renal injury, we have made little headway in therapeutic interventions that can alter the rate or degree of recovery from clinical acute tubular necrosis. The present paradigm for recovery of the renal tubule from ATN is that surviving cells from the areas bordering the injury de-differentiate, migrate into the regions of tubular denudation and proliferate to re-establish the normal tubular epithelium. In this application, we describe an entirely new and unexpected pathway for renal tubule repair, the mobilization and homing of bone marrow stem cells to the injured tubular segment. We have found that mouse adult bone marrow contains Lin-Sca-1+ stem cells that are mobilized into the circulation by transient renal ischemia, and that these cells home specifically to injured regions of the renal tubule where they differentiate into renal tubular epithelial cells. Furthermore, 1 week after the ischemic injury, these bone marrow-derived cells appear to make up the majority of the cells present in the previously necrotic tubule segments. Our hypothesis is that the adult bone marrow contains stem cells (BMSCs) that retain features similar to embryonic metanephric mesenchyme, and that ischemic renal injury can induce the homing of these cells to the kidney, where they fully differentiate and functionally incorporate into the renal tubule. Our goal is to determine how BMSCs differentiate to become renal tubular cells, including what regions of the kidney they can populate and their level of functional differentiation (SA 1), to identify the factors that regulate the mobilization and targeting of these cells to the kidney (SA 2), to culture BMSCs in vitro and determine the mechanism of their differentiation into epithelia (SA 3), and then use BMSCs to functionally repopulate the renal epithelium in models of tubular cell dysfunction. These experiments are designed to provide the functional basis for an entirely novel approach for enhancing renal tubular repair following acute injury, as well as for using stem cell transplant to deliver normal tubular cells precursors as therapy for genetically mediated tubule dysfunction. ? ?
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