The Mechanism Regulating Renal Progenitor Aging



 DESCRIPTION (provided by applicant): The kidney contains a multitude of functional units called nephrons that are built during fetal development from a mesenchymal progenitor population. Although stem-like in many aspects, these progenitors differentiate en masse before or shortly after birth. Variability in the timing of this event determines nephron endowment, with low nephron number being correlated with serious health consequences including hypertension, glomerulosclerosis, and chronic kidney disease in adulthood. The mechanisms that lead to the depletion of CM cells remain elusive. Because the progenitors contribute to their own niche we hypothesized that cell intrinsic changes within the CM dictate the collective exit from the niche. To test this hypothesis, we established a new transplantation assay of nephron progenitors to evaluate engraftment of old and young progenitors into the same young niche. We discovered proliferation rates, exit rates, adhesion properties and prolonged niche residence a were inversely correlated with age. Importantly, a few old progenitors remain in the niche for up to 7 days post engraftment, a net gain of 50% to their lifespan, but only if completely surrounded by young neighbors. We will test three hypotheses: (1) changes in Fgf20 (reduced with age) and/or mTor signaling (increased with age) are driving exit from the niche. (2) We will also test the hypothesis that age-dependent epigenetic changes lower the bar for mesenchymal to epithelial transition. (3) We posits that progressive changes in the transcriptome and translatome drive niche exit. We performed unbiased transcriptome profiling of single nephron progenitors and identified distinct age-dependent transcriptional signatures, showing changes in the translation machinery. We propose to complete the analysis by examining the changes in the translatome. The engraftment assay will determine which manipulations of candidate genes delays niche exit. We will use animal models to test of this opens the door to increasing nephron endowment in situ.