Nephron progenitor cell death elicits a limited compensatory response associated with interstitial expansion in the neonatal kidney.
Center for Molecular Medicine, Maine Medical Center Research Institute
Dis Model Mech
Animals, Animals, Newborn, Cell Count, Cell Death, Cell Proliferation, Cell Survival, Embryo, Mammalian, Gene Expression Regulation, Macrophage Colony-Stimulating Factor, Macrophages, Mice, Inbred C57BL, Nephrons, Nuclear Proteins, Stem Cells, Trans-Activators
The final nephron number in an adult kidney is regulated by nephron progenitor cell availability and collecting duct branching in the fetal period. Fetal environmental perturbations that cause reductions in cell numbers in these two compartments result in low nephron endowment. Previous work has shown that maternal dietary factors influence nephron progenitor cell availability, with both caloric restriction and protein deprivation leading to reduced cell numbers through apoptosis. In this study, we evaluate the consequences of inducing nephron progenitor cell death on progenitor niche dynamics and on nephron endowment. Depletion of approximately 40% of nephron progenitor cells by expression of diphtheria toxin A at embryonic day 15 in the mouse results in 10-20% nephron reduction in the neonatal period. Analysis of cell numbers within the progenitor cell pool following induction of apoptosis reveals a compensatory response in which surviving progenitor cells increase their proliferation and replenish the niche. The proliferative response is temporally associated with infiltration of macrophages into the nephrogenic zone. Colony stimulating factor 1 (CSF1) has a mitogenic effect on nephron progenitor cells, providing a potential explanation for the compensatory proliferation. However, CSF1 also promotes interstitial cell proliferation, and the compensatory response is associated with interstitial expansion in recovering kidneys which can be pharmacologically inhibited by treatment with clodronate liposomes. Our findings suggest that the fetal kidney employs a macrophage-dependent compensatory regenerative mechanism to respond to acute injury caused by death of nephron progenitor cells, but that this regenerative response is associated with neonatal interstitial expansion.
Muthukrishnan, Sree Deepthi; Ryzhov, Sergey; Karolak, Michele; and Oxburgh, Leif, "Nephron progenitor cell death elicits a limited compensatory response associated with interstitial expansion in the neonatal kidney." (2018). Maine Medical Center. 1462.