Rainbow Mouse Model Reveals Secrets of Kidney Regeneration

The ability of the kidney to regenerate following disease or injury has been linked to the activation of the WNT signaling pathway and the generation of segment-specific fate-restricted clones.

How the mammalian kidney generates and maintains its proximal tubules, distal tubules, and collecting ducts has been a controversial topic for researchers in this field. In the current study, investigators at Tel Aviv University (Israel) and colleagues at Stanford University (Palo Alto, CA, USA) employed the novel "rainbow mouse" model to investigate kidney regeneration at the cellular level.

The rainbow mouse is a line that was genetically engineered to express one of four alternative fluorescent reporters in each cell. These markers enabled tracing cell growth in vivo. Working with the rainbow mouse model, the investigators employed long-term in vivo genetic lineage tracing and clonal analysis of individual cells from kidneys undergoing development, maintenance, and regeneration.

The investigators reported in the May 22, 2014, issue of the journal Cell Reports that the adult mammalian kidney underwent continuous synthesis of tubules via expansions of fate-restricted clones. Kidneys recovering from damage maintained tubule synthesis through expansions of clones with segment-specific borders. Renal spheres developing in vitro from individual cells retained distinct, segment-specific fates.

Analysis of mice derived by transfer of color-marked embryonic stem cells (ESCs) into uncolored blastocysts demonstrated that nephrons were polyclonal, developing from expansions of singly fated clones. Adult renal clones were derived from Wnt-responsive precursors, and their tracing in vivo generated tubules that were segment specific.

Wnt signaling molecules regulate cell-to-cell interactions during embryogenesis. Wnt genes and Wnt signaling are also implicated in cancer. Although the presence and strength of any given effect depends on the WNT ligand, cell type, and organism, some components of the signaling pathway are remarkably conserved in a wide variety of organisms.

"Our aim was to use a new technique to analyze an old problem," said senior author Dr. Benjamin Dekel, professor of pediatrics at Tel Aviv University." No one had ever used a rainbow mouse model to monitor development of kidney cells. It was exciting to use these genetic tricks to discover that cellular growth was occurring all the time in the kidney—that, in fact, the kidney was constantly remodeling itself in a very specific mode. We were amazed to find that renal growth does not depend on a single stem cell, but is rather compartmentalized. Each part of the nephron is responsible for its own growth, each segment responsible for its own development, like a tree trunk and branches — each branch grows at a different pace and in a different direction. This study teaches us that in order to regenerate the entire kidney segments different precursor cells grown outside of our bodies will have to be employed. In addition, if we were able to further activate the WNT pathway, then in cases of disease or trauma we could activate the phenomena for growth and really boost kidney regeneration to help patients. This is a platform for the development of new therapeutics, allowing us to follow the growth and expansion of cells following treatment."

"We wanted to change the way people thought about kidneys—about internal organs altogether," said Dr. Dekel. "Very little is known even now about the way our internal organs function at the single cell level. This study flips the paradigm that kidney cells are static—in fact, kidney cells are continuously growing, all the time."

Related Links:
Tel Aviv University
Stanford University