Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Molecular Signatures of Fetal and Adult Prostate Stem Cells

ABSTRACT: The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer. A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem cells include expression profiles of Wnt, Shh and other pathways identified in stem cells of other organs, signatures of the aryl-hydrocarbon receptor, and up-regulation of components of the aldehyde dehydrogenase/retinoic acid receptor axis. There is also a significant lipid metabolism signature, marked by overexpression of lipid metabolizing enzymes and the presence of the binding motif for Srebp1. The fetal stem cell population, characterized by more rapid proliferation and self-renewal, expresses regulators of the cell cycle, such as E2f, Nfy, Tead2 and Ap2, at elevated levels, while adult stem cells show a signature in which TGF-? has a prominent role. Finally, comparison of the signatures of primitive prostate cells with previously described profiles of human prostate tumors identified stem cell molecules and pathways with deregulated expression in prostate tumors including chromatin modifiers and the oncogene, Erg. Our data indicate that adult prostate stem or progenitor cells may acquire characteristics of self-renewing primitive fetal prostate cells during oncogenesis and suggest that aberrant activation of components of prostate stem cell pathways may contribute to the development of prostate tumors. In order to identify molecules and pathways that are active in primitive prostate populations we determined the transcriptional profiles of four populations of cells: (i) fetal urogenital sinus epithelial cells, enriched in fetal prostate stem cells, (ii) Sca-1Hi, cells that express high levels of Sca-1, enriched in adult prostate stem cells, (iii) Sca-1Lo, cells that express medium to low levels of Sca-1 and are enriched in transit-amplifying cells, and (iv) Sca-1Neg, cells with no Sca expression, that represent the most mature population and have almost no in vivo regenerative potential.

ORGANISM(S): Mus musculus

SUBMITTER: Roy Blum

PROVIDER: E-GEOD-15580 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer.

Blum Roy R Gupta Rashmi R Burger Patricia E PE Ontiveros Christopher S CS Salm Sarah N SN Xiong Xiaozhong X Kamb Alexander A Wesche Holger H Marshall Lisa L Cutler Gene G Wang Xiangyun X Zavadil Jiri J Moscatelli David D Wilson E Lynette EL

PloS one 20090529 5

<h4>Background</h4>The global gene expression profiles of adult and fetal murine prostate stem cells were determined to define common and unique regulators whose misexpression might play a role in the development of prostate cancer.<h4>Methodology/principal findings</h4>A distinctive core of transcriptional regulators common to both fetal and adult primitive prostate cells was identified as well as molecules that are exclusive to each population. Elements common to fetal and adult prostate stem ...[more]

PMID: 19478945

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Project description:Isolation of prostate stem cells is crucial for understanding their biology during normal development and tumorigenesis. In this aim, we used a transgenic mouse model expressing GFP from the stem cell-specific s-SHIP promoter to mark putative stem cells during postnatal prostate development. We showed that cells identified by s-SHIP/GFP expression are present transiently during early prostate development and localize to the basal cell layer of the epithelium. These prostate s-SHIP/GFP-positive cells represent a subpopulation of the lineage-negative / CD24-positive / Sca-1-positive / CD49f-positive (LSC) cells and are capable of selfârenewal together with enhanced growth potential in sphereâforming assay in vitro, a phenotype consistent with that of a prostate stem cell population. Transplantation assays of these prostate GFP-positive cells demonstrate reconstitution of prostate ducts containing both basal and luminal cells in renal grafts. Altogether, these results demonstrate that s-SHIP promoter expression is a new marker for neonatal basal prostate cells exhibiting stem cell properties that enables prostate stem cells in situ identification and isolation via a single consistent parameter. Since the GFP-positive cell population is a small subset of basal LSC cells and is most responsible for stem-like activity, we performed transcriptional profiling of GFP-negative LSC and GFP-positive LSC cells to distinguish a basal cell profile from a tissue stem cell profile. Prostate tissue was collected from 6-day-old male mice, minced into small fragment, digested with 200 U/ml collagenase IAâS (Sigma; C5894) in Dulbeccoâs modified Eagles medium (DME, Gibco) supplemented with 10% fetal bovine serum (FBS, Hyclone) (DME-10% FBS) at 37Â°C for 60 min with gentle agitation. The digested cells were filtered through a 40-Î¼m cell strainer (BD Biosciences) washed, and resuspended in DME-10% FBS., filtered and labeled with antibodies against lineage (Ter119, CD31, CD45), CD49f and Sca-1 cell surface markers (Affymetrix ebiosciences). Labeled cells were analyzed and the GFP-negative LSC and GFP-positive-LSC populations were sorted by FACS. For each cell population, 3 independent samples were collected and analysed.

Project description:BACKGROUND: Hox genes are implicated in hematopoietic stem cell (HSC) regulation as well as in leukemia development through translocation with the nucleoporin gene NUP98. Interestingly, an engineered NUP98-HOXA10 (NA10) fusion can induce a several hundred-fold expansion of HSCs in vitro and NA10 and the AML-associated fusion gene NUP98-HOXD13 (ND13) have a virtually indistinguishable ability to transform myeloid progenitor cells in vitro and to induce leukemia in collaboration with MEIS1 in vivo. METHODOLOGY/PRINCIPAL FINDINGS: These findings provided a potentially powerful approach to identify key pathways mediating Hox-induced expansion and transformation of HSCs by identifying gene expression changes commonly induced by ND13 and NA10 but not by a NUP98-Hox fusion with a non-DNA binding homedomain mutation (N51S). The gene expression repertoire of purified murine bone marrow Sca-1+Lin- cells transduced with retroviral vectors encoding for these genes was established using the Affymetrix GeneChip MOE430A. Approximately seventy genes were differentially expressed in ND13 and NA10 cells that were significantly changed by both compared to the ND13(N51S) mutant. Intriguingly, several of these potential Hox target genes have been implicated in HSC expansion and self-renewal, including the tyrosine kinase receptor Flt3, the prion protein, Prnp, hepatic leukemia factor, Hlf and Jagged-2, Jag2. CONCLUSIONS: In conclusion this study has identified several novel Hox downstream target genes and provides important new leads to key regulators of the expansion and transformation of hematopoietic stem cells by Hox. Experiment Overall Design: Adult murine bone marrow cells transduced with vectors carrying ND13, NA10, ND13(N51S) or an empty GFP control vector (MIG) were isolated on the basis of GFP expression by FACS 24 hours post-transduction. Viable transduced cells were further enriched for primitive hematopoietic cells by exclusion of cells expressing linage markers (Gr-1, B220, Ter-119, CD4, CD5 and CD8) and selection for cells expressing the stem cell antigen-1 (Sca-1). Three independent experiments were performed for each of the four different conditions included in the study.

Dataset Information

Molecular Signatures of Fetal and Adult Prostate Stem Cells

Publications

Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer.

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