find more The adult mammalian kidney is an organ with very l

The adult mammalian kidney is an organ with very low cell cycling during homeostasis but remarkable proliferating capacity after injury. It is still unresolved whether the kidney contains bona fide stem cells. Humphreys et al. (2008) genetically marked cells using Six2, a transcription factor expressed in embryonic kidney epithelial stem cells, and fate-mapped their progeny during adult kidney regeneration; they found that new epithelial cells after injury derived from cells of the same embryonic lineage. Although this study was interpreted to indicate that stochastic proliferation of terminally differentiated cells generates the new cells needed for kidney repair and that thus the adult kidney does not contain stem cells, it could not exclude that resident stem cell pools in the adult kidney might themselves be derived from the Six2 compartment. During kidney regeneration from injury, Berger et al. (2014) performed cell-lineage analysis of a postulated proximal tubular epithelial stem cell population that was genetically labeled by doxycycline administration. When labeling was done before kidney injury (KI) the labeled cells did not expand, suggesting that these scattered proximal tubular cells were not stem/precursor cells. Similarly, labeling proximal tubular cells before injury followed by injury showed that there was no dilution of the label, which was interpreted as favoring the absence of a progenitor pool (Kusaba et al., 2014). Cell-lineage tracing has also been applied to investigate the origin of podocytes, a particular target of many kidney diseases. Several lines of evidence suggested that adult podocytes might derive from the parietal epithelial cells lining Bowman\'s find more (Ronconi et al., 2009), and Appel et al. (2009) found that a transgenic mouse with podocalyxin (expected to identify podocytes) unexpectedly expressed the transgene in the parietal epithelial cells. Inducible gene tagging of these cells with doxycycline showed that they generated podocytes but only in mice of young age, a time when kidney size increases dramatically. More recently, Rinkevich et al. (2014) used an unbiased approach to mark single-cell clones in the adult kidney and found that they generated long tubular segments along the nephron, strongly suggesting the presence of specialized progenitor cells that were segment specific in the nephron. To search for stem cells in the adult kidney, we originally used the observation that many organ-specific stem cells cycle at very low rates, and with S-phase markers identified a population of low-cycling cells in the adult kidney papilla (Oliver et al., 2004, 2009). Since the cells retain these markers for long periods, we termed them papillary label-retaining cells (pLRCs). We found that following KI many of the pLRCs proliferated and occasionally located in other parts of the kidney, suggesting their involvement in organ regeneration. We thus postulated that the kidney papilla is a niche for progenitor/stem cells. However, as pLRCs divide, the S-phase label marking them dilutes into their daughter cells, and their identification has remained elusive. Genetic lineage tracing of the pLRCs would allow this, but a specific marker was lacking. To obtain such a marker, we isolated live pLRCs and appropriate control cells from the H2B-GFP mouse and analyzed their transcriptional profile. After selecting a small number of genes overexpressed in the pLRCs, we performed qPCR analysis of the candidate genes and immunolocalized their encoded proteins in the kidney. Among these, protrudin, a cytoplasmic protein encoded by Zfyve27, identified a population of pLRCs. We then used it to perform lineage analysis of these cells by generating Zfyve27-CreERT2 transgenic mice. Our results show that in the adult kidney Zfyve27-CreERT2-marked cells preferentially located in the upper part of the papilla. These cells do not generate progeny during homeostasis and thus appear not to contribute to normal kidney maintenance. However, after KI, particularly if severe, these cells are activated and follow a complex program of proliferation, migration, and morphogenesis generating multiple and long tubular segments located preferentially in the kidney medulla, indicating a critical role in the repair of this region of the kidney. Our results thus suggest that different parts of the kidney have different progenitor cell pools.