Label-retaining cells of the bladder: candidate urothelial stem cells

Kurzrock, Eric A.; Lieu, Deborah K.; DeGraffenried, Lea Ann; Chan, Chun Man; Isseroff, Roslyn Rivkah

doi:10.1152/ajprenal.00533.2007

Cited by 128 publications

(124 citation statements)

References 41 publications

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“…Urothelial cells express cytokeratin 14, a known marker of epithelial progenitors (33), and thus share striking similarities with bladder urothelial progenitors (12). Of notice, they have a low proliferation index in physiological conditions and smooth muscle cells are located in close contact, as previously shown (5).…”

Section: Discussionmentioning

confidence: 56%

Intrarenal urothelium proliferation: an unexpected early event following ischemic injury

Vinsonneau

Girshovich

M’Rad

et al. 2010

American Journal of Physiology-Renal Physiology

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Identification of renal cell progenitors and recognition of the events contributing to cell regeneration following ischemia-reperfusion injury (IRI) are a major challenge. In a mouse model of unilateral renal IRI, we demonstrated that the first cells to proliferate within injured kidneys were urothelial cells expressing the progenitor cell marker cytokeratin 14. A systematic cutting of the injured kidney revealed that these urothelial cells were located in the deep cortex at the corticomedullary junction in the vicinity of lobar vessels. Contrary to multilayered bladder urothelium, these intrarenal urothelial cells located in the upper part of the medulla constitute a monolayered barrier and express among uroplakins only uroplakin III. However, like bladder progenitors, intrarenal urothelial cells proliferated through a FGF receptor-2 (FGFR2)-mediated process. They strongly expressed FGFR2 and proliferated in vivo after recombinant FGF7 administration to control mice. In addition, IRI led to FGFR phosphorylation together with the selective upregulation of FGF7 and FGF2. Conversely, by day 2 following IRI, renal urothelial cell proliferation was significantly inhibited by FGFR2 antisense oligonucleotide administration into an intrarenal urinary space. Of notice, no significant migration of these early dividing urothelial cells was detected in the cortex within 7 days following IRI. Thus our data show that following IRI, proliferation of urothelial cells is mediated by the FGFR2 pathway and precedes tubular cell proliferation, indicating a particular sensitivity of this structure to changes caused by the ischemic process.

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Section: Discussionmentioning

confidence: 56%

Intrarenal urothelium proliferation: an unexpected early event following ischemic injury

Vinsonneau

Girshovich

M’Rad

et al. 2010

American Journal of Physiology-Renal Physiology

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“…These similarities may reflect the presence of urothelial basal cells and their corollary, the basal/myoepithelial cells of the breast. In both tissues, these basal cells represent a multipotent "stem/progenitor cell" population (35,36) and their similar functional roles may explain their similar molecular profiles.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology

Damrauer

Hoadley

Chism

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

775

777

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We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of highgrade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtypespecific therapies, will be of interest.I n the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women, with 72,570 new cases and 15,210 deaths expected in 2013 (1). Bladder cancer is heterogeneous and can be histologically divided into low-grade and high-grade disease. Whereas low-grade tumors are almost invariably noninvasive (Ta), high-grade tumors can be classified based on invasion into the muscularis propria of the bladder, as non-muscle invasive bladder cancer (NMIBC; Tis, Ta, T1) or muscle invasive bladder cancer (MIBC; ≥T2). Low-grade tumors are associated with a high rate of recurrence but an excellent overall prognosis, with a 5-y survival in the range of 90%. In contrast, high-grade MIBC has a relatively poor 5-y overall survival, 68% for T2 and decreasing to 15% for non-organ-confined disease (i.e., pT3 and pT4) (1, 2).Along with divergent pathologies and prognosis, low-grade and high-grade UCs are associated with distinct genetic alterations. For example, low-grade UCs are enriched for activating mutations in fibroblast growth factor 3 (FGFR3), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and inactivating lysine (K)-specific demethylase 6A (KDM6A) mutations, whereas high-grade, muscle-invasive tumors are enriched for tumor protein p53 (TP53) and retinoblastoma 1 (RB1) pathway alterations (3-10).Several reports have examined the gene expression profiles of primary bladder tumors. From these studies, it is apparent that low-grade noninvasive and high-grade muscle-invasive tumors harbor distinct gene expression patterns, and that further molecular subsets can be identified within low-grade and high-grade tumors (5,(11)(12)(13)(14). Moreover, a number of gene signatures have been developed that can predict tumor stage, lymph node metastases, and bladder cancer progression (11-13, 15-18). There are established gene expression patterns that differentiate lowgrade and high-grade tumors;...

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“…Due to the lack of specific markers, potential stem cells in the urinary bladder have tentatively been identified using the ''label-retaining cell (LRC)'' strategy [7]. In this study, the authors intraperitoneally injected thymidine analog, 5-bromo-2-deoxyuridine (BrdU), into 6-week-old rats daily for 4 consecutive days.…”

mentioning

confidence: 99%

Presence of Stem/Progenitor Cells in the Rat Penis

Lin

Alwaal

Zhang

et al. 2015

Stem Cells and Development

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Tissue resident stem cells are believed to exist in every organ, and their identification is commonly done using a combination of immunostaining for putative stem cell markers and label-retaining cell (LRC) strategy. In this study, we employed these approaches to identify potential stem cells in the penis. Newborn rats were intraperitoneally injected with thymidine analog, 5-ethynyl-2-deoxyuridine (EdU), and their penis was harvested at 7 h, 3 days, 1 week, and 4 weeks. It was processed for EdU stains and immunofluorescence staining for stem cell markers A2B5, PCNA, and c-kit. EdU-positive cells were counted for each time point and co-localized with each stem cell marker, then isolated and cultured in vitro followed by their characterization using flowcytometry and immunofluorescence. At 7 h post-EdU injection, 410 -105.3 penile corporal cells were labeled in each cross-section (*28%). The number of EdU-positive cells at 3 days increased to 536 -115.6, while their percentage dropped to 25%. Progressively fewer EdU-positive cells were present in the sacrificed rat penis at longer time points (1 and 4 weeks). They were mainly distributed in the subtunic and perisinusoidal spaces, and defined as subtunic penile progenitor cells (STPCs) and perisinusoidal penile progenitor cells (PPCs). These cells expressed c-kit, A2B5, and PCNA. After culturing in vitro, only *0.324% corporal cells were EdUlabeled LRCs and expressed A2B5/PCNA. Therefore, labeling of penis cells by EdU occurred randomly, and label retaining was not associated with expression of c-kit, A2B5, or PCNA. The penile LRCs are mainly distributed within the subtunic and perisinusoidal space.

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Label-retaining cells of the bladder: candidate urothelial stem cells

Cited by 128 publications

References 41 publications

Intrarenal urothelium proliferation: an unexpected early event following ischemic injury

Intrarenal urothelium proliferation: an unexpected early event following ischemic injury

Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology

Presence of Stem/Progenitor Cells in the Rat Penis

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