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Normal human prostate (NHP) epithelial cells: Senescent and immortalized cells compared to young progenitors

ABSTRACT: Normal human prostate (NHP) epithelial cells undergo senescence in vitro and in vivo, but the underlying molecular mechanisms remain incompletely understood. Here we first show that multiple primary strains of NHP cells are all immunophenotyped as CK5+/CK18+CD44+α2β1+p63+hTERT+ progenitor cells, which gradually lose progenitor markers as they lose proliferative capacity. NHP cell senescence involves loss of telomerase expression, upregulation of p16, and activation of p53. Using genetically defined manipulations of these three signaling pathways, we show that p16 is the primary determinant of the NHP cell proliferative capacity and hTERT is required for unlimited proliferative lifespan. Hence, suppression of 16 alone significantly extends NHP cell lifespan but both p16 inhibition and hTERT are required to immortalize NHP cells. Importantly, the immortalized NHP cells are normal progenitors that possess the ability to differentiate into functional prostatic glands containing both basal and luminal cells and, frequently, neuroendocrine cells. The immortalized NHP cells possess gene expression profiles characteristic of proliferating progenitor cells. Our studies shed light on the molecular mechanisms regulating the proliferative lifespan of NHP progenitor cells and provide direct evidence that basal-like progenitor cells can regenerate the entire prostatic glands in vivo. The availability of these cells should facilitate future studies of prostate cancer development. Further processed data linked below as Supplementary files. TestvsControl: corresponding GSM# 3vs1: GSM266720, 721, 722 4vs1: GSM266727, 730, 731 5vs1: GSM266732, 733, 734 7avs1: GSM266735, 736, 737 9vs1: GSM266772, 773, 812 11vs1: GSM266813, 816, 823 13vs1: GSM266824, 826, 828 Note: The 'TestvsControl' comparisons report the top 100 up- or down-regulated genes. The numeric designations (1 to 13) are used in the corresponding manuscript. The 'SignificantGenes' lists were used in clustering analysis. Keywords: Cell type comparison (senscent and immortalized NHP cells compared to young NHP progenitors)

ORGANISM(S): Homo sapiens

PROVIDER: GSE10570 | GEO | 2008/10/09

SECONDARY ACCESSION(S): PRJNA107827

REPOSITORIES: GEO

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Project description:Tissue remodeling or regeneration is believed to initiate from organ-specific stem and/or progenitor cells. We report here the establishment of two spontaneously immortalized adult human benign prostate epithelial cell lines, NHPrE1 and BHPrE1. NHPrE1CD133(++)/CD44(++)/OCT4(++)/CK14(+++) was characterized as a putative progenitor cell, and BHPrE1CD133(+)/CD44(+)/OCT4(+)/CK14(++) as a putative intermediate cell. aCGH analysis demonstrated a largely intact diploid karyotype with DNA amplification of PTEN in NHPrE1 or Beta-Catenin in BHPrE1 cells, respectively. A tissue recombination-xenografting model was utilized to compare remodeling of human prostatic tissues in vivo by the NHPrE1 and BHPrE1 cell lines and their parental primary cells. A series of tissue recombinants, made by mixing different ratios of human prostatic epithelial cells and inductive rat urogenital sinus mesenchyme (UGM), were grafted to the renal capsule of SCID mice. Both cell lines were able to regenerate ductal/acinar structures in vivo containing basal and luminal epithelial populations confirmed by the expression of appropriate cytokeratin profiles. Androgen receptor (AR), prostate specific antigen (PSA), and 15-lipoxigenase-2 (15-LOX-2) expression were appropriately expressed in the regenerated epithelial structures. Regeneration of benign human prostatic ductal/acinar architecture could be achieved using as few as 10 NHPrE1 cells while 200,000 BHPrE1 cells were required to achieve prostatic structure. This suggests a greater proportion of progenitor cells in NHPrE1 facilitated regeneration of prostatic morphology and function. These cell lines provide important data on progenitor and intermediate cell phenotypes and represent significant new tools for the elucidation of molecular mechanisms of human prostatic regeneration, pathogenesis and carcinogenesis. Two channel CGH from Agilent platform was used to detect DNA amplification or deletion in genomic samples from NHPrE1 and BHPrE1 cell lines. A common pooled normal DNA refernce was used.

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Normal human prostate (NHP) epithelial cells: Senescent and immortalized cells compared to young progenitors

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