Identification of adult nephron progenitors capable of kidney regeneration in zebrafish

Abstract

Fish can regenerate nephrons — the functional units of the kidney — following kidney injury, whereas adult mammals lack this ability. A previously unknown type of kidney cell responsible for this regeneration has now been discovered in adult zebrafish, where they are found in small aggregations throughout the kidney. When as few as 10–20 of these progenitor cells are transplanted into injured adult kidneys, they engraft and form new, functional nephrons. This suggests that it might be possible to identify an equivalent regenerative cell in humans for therapeutic purposes. Fish can regenerate nephrons (the functional units of the kidney) de novo after kidney injury, whereas adult mammals lack this ability. This study identifies a pool of self renewing nephron stem/progenitor cells that are responsible for nephrogenesis during kidney growth and regeneration in zebrafish. The findings might provide an insight into how mammalian renal regeneration may be therapeutically activated. Loss of kidney function underlies many renal diseases1. Mammals can partly repair their nephrons (the functional units of the kidney), but cannot form new ones2,3. By contrast, fish add nephrons throughout their lifespan and regenerate nephrons de novo after injury4,5, providing a model for understanding how mammalian renal regeneration may be therapeutically activated. Here we trace the source of new nephrons in the adult zebrafish to small cellular aggregates containing nephron progenitors. Transplantation of single aggregates comprising 10–30 cells is sufficient to engraft adults and generate multiple nephrons. Serial transplantation experiments to test self-renewal revealed that nephron progenitors are long-lived and possess significant replicative potential, consistent with stem-cell activity. Transplantation of mixed nephron progenitors tagged with either green or red fluorescent proteins yielded some mosaic nephrons, indicating that multiple nephron progenitors contribute to a single nephron. Consistent with this, live imaging of nephron formation in transparent larvae showed that nephrogenic aggregates form by the coalescence of multiple cells and then differentiate into nephrons. Taken together, these data demonstrate that the zebrafish kidney probably contains self-renewing nephron stem/progenitor cells. The identification of these cells paves the way to isolating or engineering the equivalent cells in mammals and developing novel renal regenerative therapies.