Genetic tracing of the epithelial lineage during mammalian kidney repair

Abstract

Developing new therapeutic approaches to treat acute kidney injury requires a detailed understanding of endogenous cellular repair. Genetic fate mapping defines cellular hierarchies in vivo and we used this technique to assess a possible contribution of non-epithelial stem cells to renal repair after ischemic injury. Mice with efficient labeling of renal epithelial cells, but not non-epithelial interstitial cells, were subjected to a single cycle or sequential cycles of kidney injury and repair. No dilution of the epithelial cell fate marker was observed despite robust epithelial cell proliferation. Thus, non-tubular cells do not have the ability to migrate across the basement membrane and differentiate into epithelial cells in this model. Instead, surviving tubular epithelial cells are responsible for repair of the damaged nephron. Future studies will need to distinguish between uniform dedifferentiation and proliferation of all epithelial cells after injury versus selective expansion of an intratubular epithelial stem cell.