(L to R) Andy McMahon, Todd Valerius, Josh Mugford, and Akio Kobayashi
The kidney is a remarkable organ. Its actions maintain an appropriate water/salt balance within tissue fluids, remove nitrogenous waste and modify blood composition and blood pressure. The rise in kidney disease, now the third biggest cost within the United States health care sector, makes an understanding of how this organ is built and repaired an urgent priority.
The basic functional unit of the kidney is the nephron. The entire plasma component of the blood is filtered through an epithelial network of nephrons several times per hour. In humans, there are approximately 500,000 nephrons per kidney; our experimental surrogate, the mouse, has closer to 13,000. Nephrons are generated over an extensive period of fetal development through an inductive process that couples branching growth of the future network of the urine-conducting collecting duct system with the formation of nephron precursors, the renal vesicles. These simple, epithelial structures are generated from a mesenchymal progenitor population in a poorly-understood iterative process.
In the new work, Akio Kobayashi, Todd Valerius and Josh Mugford in the the McMahon lab have collaborated with the Oliver group at St. Jude Children’s Hospital to explore the cellular principles and molecular pathways orchestrating mammalian nephrogenesis. Using genetic systems, they identified the nephron progenitor pool as a subset of the mesenchymal populations within the developing kidney demarcated by expression of the transcriptional regulator Six2. Like a stem cell, a Six2+ cell can undergo self-renewal, thereby replenishing the nephron progenitor pool. Alternatively, cells can lose Six2 activity and commit to renal vesicle fates; ultimately multiple mature nephron structures may arise from descendants of a single Six2+ progenitor. This commitment step is regulated by canonical Wnt-signaling. Several lines of evidence have previously identified Wnt9b as the key early factor. This Wnt9b action appears to be countered by Six2, maintaining a progenitor pool. Consequently, Six2 action permits new rounds of nephron formation and the establishment of a full complement of nephrons. Self-renewal activity is limited to fetal life; the Six2 population is lost on birth and with it the capacity to generate new nephrons. Thus, nephron regeneration rather than de novo nephrogenesis is the normal option for repair of damaged nephrons in the adult.
Read more in Cell Stem Cell
