Proliferation and Migration of Label-Retaining Cells of the Kidney Papilla

Abstract

The kidney papilla contains a population of cells with several characteristics of adult stem cells, including the retention of proliferation markers during long chase periods (i.e., they are label-retaining cells [LRCs]). To determine whether the papillary LRCs generate new cells in the normal adult kidney, we examined cell proliferation throughout the kidney and found that the upper papilla is a site of enhanced cell cycling. Using genetically modified mice that conditionally expressed green fluorescence protein fused to histone 2B, we observed that the LRCs of the papilla proliferated only in its upper part, where they associate with "chains" of cycling cells. The papillary LRCs decreased in number with age, suggesting that the cells migrated to the upper papilla before entering the cell cycle. To test this directly, we marked papillary cells with vital dyes in vivo and found that some cells in the kidney papilla, including LRCs, migrated toward other parts of the kidney. Acute kidney injury enhanced both cell migration and proliferation. These results suggest that during normal homeostasis, LRCs of the kidney papilla (or their immediate progeny) migrate to the upper papilla and form a compartment of rapidly proliferating cells, which may play a role in repair after ischemic injury. Adult stem cells contribute to organ repair after injury 1-5 ; however, their contribution to normal tissue homeostasis by the generation of a continuous supply of new cells has not been readily apparent, except in tissues with relatively simple architecture and high rate of cell turnover, such as the skin and the intestinal epithelia. 1,6 In addition, recent studies have shown that in some organs, precursor cells responsible for homeostatic cell turnover are different from those responsible for cell replacement after injury. For example, stem cells in the bulge of the hair follicle contribute to wound repair, 5 but normal cell turnover of the epidermis is maintained by a distinct progenitor population located in the interfollicular epidermis. 7 In the olfactory neuroepithelium, a site of continuous neurogenesis under normal conditions in the adult, new neurons are generated by the globose basal cells that reside in the basal germinal zone of the pseudostratified olfactory neuroepithelium; however, after extensive tissue damage, another population of cells (horizontal basal cells) starts proliferating and generates several cell types. 8 Finally, ␤ cells of the pancreas are maintained by proliferation of terminally differentiated ␤ cells, 9,10 but in injured pancreas, multipotent progenitor cells can give rise to ␤ cells. 11 The normal adult kidney has a very low rate of cell turnover, 12 but it is capable of responding quickly to injury by generating new cells to replace

Characterization and Fate of Telomerase-expressing Epithelia during Kidney Repair

“…19 If true, there may be an increase in the number of mTert-GFP cells as they divide and migrate to the site of repair in the outer medulla, as has been proposed for putative papillary stem cells. 19 To test this hypothesis, we next subjected mTert-GFP mice to ischemia-reperfusion injury and counted the number of mTert-GFP cells in all kidney regions at 24 or 48 hours after injury. BrdU incorporation was assessed in parallel, to verify kidney injury and to ask whether mTert-GFP cells were selectively recruited to proliferate by an injury stimulus.…”

“…30 Papillary mTert mRNA Is Increased During Repair A role for kidney stem or progenitor cells in kidney repair after acute injury has been proposed but remains controversial and largely unproven. 15,19 To investigate a possible role of mTert-expressing cells in kidney repair, we next assessed the expression pattern of mTert mRNA after bilateral ischemia-reperfusion injury. Indeed, mTert mRNA has been reported as a potential kidney injury biomarker because it was found to be upregulated in mRNA isolated from whole kidney; however, regional differences in mTert expression were not examined.…”

“…Slowly cycling, label-retaining cells have been identified in tubular epithelium of the papilla and proposed to represent a stem-cell population. 18,19 Evidence supporting other candidate intratubular stem-cell markers includes nFATc1 expression, proximal tubule label retention, Oct4 expression, and podocalyxin promoter activity. 20 -24 Finally, the identification of putative podocyte progenitors in parietal epithelium has led to the notion that regional kidney stem cells might exist.…”

Development of the kidney medulla

“…8 In addition, the renal papilla is a niche for adult kidney stem cells which may play a role in repair after ischemic kidney injury. 17,18 Developmental Aspects of Medullary Morphogenesis Development of collecting ducts. Morphologic development of collecting ducts.…”

Renal organogenesis

“…However, in the case of UUO, a papillary interstitial population is reported to migrate into the cortex and may play either a humoral or transdifferentiative role in the ensuing repair. 49 Whether this represents a true facultative response or not, distinct patterns of gene expression do exist depending upon the damage model being examined. Having much more extensively characterized the temporospatial gene expression profile of the developing and adult kidney, the time is ripe for a more an extension of such analyses into distinct renal disease states.…”