Unveiling the biology of collecting duct epithelium repair and regeneration

The healthy functioning of the kidney requires the orchestrated action of its two functional units, nephrons and the collecting duct system (CD). Therefore malfunction of either of these two essential compartments can lead to kidney failure. Diseases affecting the collecting duct system (CD), congenital abnormalities of the kidney and urinary tract (CAKUTs), are the most frequent cause of End-Stage Renal Disease (ESRD) in children. At this stage, the only available therapeutic options for treating kidney failure are dialysis or organ transplantation. Given the fact that only one in three patients will receive a transplant, and that dialysis comes with a high risk of mortality, the study of the mechanisms underlying the repair and regeneration of the collecting duct system is vital because it will facilitate new therapeutic strategies for treating kidney disease which are available to more people. The CD system originates from one of the two progenitor populations which give rise to the kidney, the ureteric bud (UB). The formation of the UB is a substantial part of the nephrogenesis process, and develops into a branched tree-like structure which will ultimately form the ducts of the urinary collecting system. This PhD thesis investigates recent concepts in normal kidney organogenesis, repair, and regeneration, and focuses on the CD system. In the first part of this research, we investigated the capacity of an endogenous kidney mesenchymal stem cell population (k-MSC), previously reported by our laboratory, which both arose from the collecting duct epithelium and also then integrated into the same compartment. To this end, we generated and examined the functional capacity of Pkd1 defective k-MSCs to trigger autosomal dominant polycystic kidney disease (ADPKD) into wild type mice. Given that micro-injection of double transgenic k-MSCsPkd1del2-4/TMTO+ did not produce significant evidence for cyst formation in the recipient mice, we therefore ruled out the possibility that k-MSCs represent a preferable population for effecting repair. Nevertheless, we showed the capacity to generate k-MSCs with mutant genes, which may prove useful as cellular models of human diseases