Role of Renal and Endothelial Progenitors in Fetal Kidney Reconstitution

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Project 2 proposes to characterize, isolate, and propagate renal progenitor cells from developing human and from nonhuman primate kidneys. The purpose of these experiments is to enable reconstitution and repair of the diseased, damaged, but developing fetal kidney, by transplanting healthy progenitor cells with the capacity to differentiate into cell types and tissue that will repopulate and reconstitute the affected organ. This is a novel and clinically relevant proposal. Work to date in the field has focused on describing changes in the fetal kidney when obstructed, but these efforts have largely been restricted to the postnatal rodent kidney. Our fetal monkey model of unilateral ureteric obstruction is arguably the best model available to study this disease and strategies to treat it. The proposal is driven by the fact that the clinical condition of fetal urinary tract obstruction is one of the most important conditions affecting young children with kidney disease. The work proposed in this application brings together the support and expertise of a number of leaders in the field of stem and progenitor cell biology, fetal kidney disease, and fetal models of disease and intervention. At the successful completion of the studies proposed in this Project we are hopeful that we will be poised to embark upon potential intervention trials in the human fetus with lower urinary tract obstruction. Presently in many centers across North America, fetuses are selected for invasive in utero fetal urinary tract shunting based upon antenatal maternal ultrasound imaging. The collective results of these interventions have been somewhat disappointing due in part to the non-standardized patient selection, to the inaccuracies of in utero diagnosis, and to an as-yet-complete understanding of the pathogenesis of renal damage in urinary tract obstruction. While in utero relief of the obstructed kidney during the critical time of nephrogenesis is necessary to optimize outcome, it appears that it is likely not sufficient. Experiments proposed using human renal progenitor cells in obstructed nonhuman primate kidneys brings us as close as we can to the next step of intervention in humans. These next steps will be guided by the results of this proposal and by the subsequent development of well-designed randomized controlled trials in human fetuses.