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Estrogen receptor ? activation impairs prostatic regeneration by inducing apoptosis in murine and human stem/progenitor enriched cell populations.

ABSTRACT: Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor ? (ER?) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ER? agonist (8?-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells. Furthermore, agonist treatment attenuates clonogenicity and self-renewal of murine prostatic stem/progenitor cells and depletes both murine (Lin(-)Sca1(+)CD49f(hi)) and human (CD49f(hi)Trop2(hi)) prostatic basal cells. Finally, we demonstrate the combined added benefits of selective stimulation of ER?, including the induction of cell death in quiescent post-castration tissues. Subsequent to castration ER?-induces further apoptosis in basal, luminal and intermediate cells. Our results reveal a novel benefit of ER? activation for prostate disease and suggest that combining selective activation of ER? with androgen-deprivation may be a feasible strategy to target stem cells implicated in the origin of prostatic disease.

SUBMITTER: Hussain S

PROVIDER: S-EPMC3393688 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Estrogen receptor β activation impairs prostatic regeneration by inducing apoptosis in murine and human stem/progenitor enriched cell populations.

Hussain Shirin S Lawrence Mitchell G MG Taylor Renea A RA Lo Camden Yeung-Wah CY Frydenberg Mark M Ellem Stuart J SJ Furic Luc L Risbridger Gail P GP

PloS one 20120710 7

Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor β (ERβ) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERβ agonist (8β-VE2) administra ...[more]

PMID: 22808245

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Project description:Adequate bony support is the key to re-establish both function and esthetics in the craniofacial region. Autologous bone grafting has been the gold standard for regeneration of problematic large bone defects. However, poor graft availability and donor-site complications have led to alternative bone tissue-engineering approaches combining osteoinductive biomaterials and three-dimensional cell aggregates in scaffolds or constructs. The goal of the present study was to generate novel cell aggregate-loaded macroporous scaffolds combining the osteoinductive properties of titanium dioxide (TiO2) with hydroxyapatite-gelatin nanocomposites (HAP-GEL) for regeneration of craniofacial defects. Here we investigated the in vivo applicability of macroporous (TiO2)-enriched HAP-GEL scaffolds with undifferentiated and osteogenically differentiated multipotent adult progenitor cell (MAPC and OD-MAPC, respectively) aggregates for calvaria bone regeneration. The silane-coated HAP-GEL with and without TiO2 additives were polymerized and molded to produce macroporous scaffolds. Aggregates of the rat MAPC were precultured, loaded into each scaffold, and implanted to rat calvaria critical-size defects to study bone regeneration. Bone autografts were used as positive controls and a poly(lactic-co-glycolic acid) (PLGA) scaffold for comparison purposes. Preimplanted scaffolds and calvaria bone from pig were tested for ultimate compressive strength with an Instron 4411(®) and for porosity with microcomputerized tomography (?CT). Osteointegration and newly formed bone (NFB) were assessed by ?CT and nondecalcified histology, and quantified by calcium fluorescence labeling. Results showed that the macroporous TiO2-HAP-GEL scaffold had a comparable strength relative to the natural calvaria bone (13.8±4.5?MPa and 24.5±8.3?MPa, respectively). Porosity was 1.52±0.8?mm and 0.64±0.4?mm for TiO2-HAP-GEL and calvaria bone, respectively. At 8 and 12 weeks postimplantation into rat calvaria defects, greater osteointegration and NFB were significantly present in the TiO2-enriched HAP-GEL constructs with OD-MAPCs, compared to the undifferentiated MAPC-loaded constructs, cell-free HAP-GEL with and without titanium, and PLGA scaffolds. The tissue-engineered TiO2-enriched HAP-GEL constructs with OD-MAPC aggregates present a potential useful therapeutic approach for calvaria bone regeneration.

Dataset Information

Estrogen receptor ? activation impairs prostatic regeneration by inducing apoptosis in murine and human stem/progenitor enriched cell populations.

Publications

Estrogen receptor β activation impairs prostatic regeneration by inducing apoptosis in murine and human stem/progenitor enriched cell populations.

Similar Datasets

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