Slow-Cycling Cells in Renal Papilla

Abstract

A fundamental goal of kidney stem cell models in regenerative medicine is to harness the kidney's prodigious capacity for endogenous repair to develop new therapeutic strategies. Despite progress in understanding kidney injury and repair mechanisms, few regenerative therapies to treat human kidney injury are on the horizon. In part, this reflects the kidney's complex architecture and cellular heterogeneity, a shortage of validated stem cell markers, slow homeostatic cell turnover, and the lack of robust transplantation assays. These factors combine to slow our ability to decipher cellular hierarchies in adult tissue repair and complicate the search for adult stem and progenitor cells. The renal papilla has attracted interest as a potential niche for kidney stem cell since Oliver et al. 1 originally identified this kidney region as a site of slowly cycling cells, defined by retention of the DNA analogue 5-bromo-2-deoxyuridine (BrdU) after a short postnatal pulse followed by a long chase. Because subsequent cell divisions in the absence of label dilute the incorporated BrdU, only cells with the lowest replication profile are detected (label-retaining cells [LRCs]), and this approach has been used in other organs to enrich for stem cells that typically divide slowly. Importantly, the specificity and sensitivity of BrdU label retention is undefined for solid tissues and, in fact, is remarkably low for hematopoietic stem cells, the best characterized adult stem cell pool. For example, <6% of hematopoietic stem cells retain BrdU and <0.5% of BrdU-retaining hematopoietic cells are hematopoietic stem cells.2 Other factors recommend the papilla as a potential kidney stem cell niche beyond the residence of LRCs. Papilla has low oxygen tension and hypoxia may protect stem cells against DNA damage. There is preferential expression of genes known to regulate other stem cells in the renal papilla, including Wnt and Hedgehog ligands.3,4 …