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      Secreted microvesicular miR‐31 inhibits osteogenic differentiation of mesenchymal stem cells

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          Summary

          Damage to cells and tissues is one of the driving forces of aging and age‐related diseases. Various repair systems are in place to counteract this functional decline. In particular, the property of adult stem cells to self‐renew and differentiate is essential for tissue homeostasis and regeneration. However, their functionality declines with age (Rando, 2006). One organ that is notably affected by the reduced differentiation capacity of stem cells with age is the skeleton. Here, we found that circulating microvesicles impact on the osteogenic differentiation capacity of mesenchymal stem cells in a donor‐age‐dependent way. While searching for factors mediating the inhibitory effect of elderly derived microvesicles on osteogenesis, we identified miR‐31 as a crucial component. We demonstrated that miR‐31 is present at elevated levels in the plasma of elderly and of osteoporosis patients. As a potential source of its secretion, we identified senescent endothelial cells, which are known to increase during aging in vivo (Erusalimsky, 2009). Endothelial miR‐31 is secreted within senescent cell‐derived microvesicles and taken up by mesenchymal stem cells where it inhibits osteogenic differentiation by knocking down its target Frizzled‐3. Therefore, we suggest that microvesicular miR‐31 in the plasma of elderly might play a role in the pathogenesis of age‐related impaired bone formation and that miR‐31 might be a valuable plasma‐based biomarker for aging and for a systemic environment that does not favor cell‐based therapies whenever osteogenesis is a limiting factor.

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          Telomerase reactivation reverses tissue degeneration in aged telomerase deficient mice

          An ageing world population has fueled interest in regenerative remedies that may stem declining organ function and maintain fitness. Unanswered is whether elimination of intrinsic instigators driving age-associated degeneration can reverse, as opposed to simply arrest, various afflictions of the aged. Such instigators include progressively damaged genomes. Telomerase deficient mice have served as a model system to study the adverse cellular and organismal consequences of wide-spread endogenous DNA damage signaling activation in vivo 1. Telomere loss and uncapping provokes progressive tissue atrophy, stem cell depletion, organ system failure, and impaired tissue injury responses1. Here, we sought to determine whether entrenched multi-system degeneration in adult mice with severe telomere dysfunction can be halted or possibly reversed by reactivation of endogenous telomerase activity. To this end, we engineered a knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-Estrogen Receptor (TERT-ER) under transcriptional control of the endogenous TERT promoter. Homozygous TERT-ER mice display short dysfunctional telomeres and sustain increased DNA damage signaling and classical degenerative phenotypes upon successive generational matings and advancing age. Telomerase reactivation in such late generation TERT-ER mice extends telomeres, reduces DNA damage signaling and associated cellular checkpoint responses, allows resumption of proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs including testes, spleens and intestines. Notably, somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, DCX+ newborn neurons, and Olig2+ oligodendrocyte populations. Consistent with the integral role of SVZ neural progenitors in generation and maintenance of olfactory bulb interneurons2, this wave of telomerase-dependent neurogenesis resulted in alleviation of hyposmia and recovery of innate olfactory avoidance responses. Accumulating evidence implicating telomere damage as a driver of age-associated organ decline and disease risk1,3 and the dramatic reversal of systemic degenerative phenotypes in adult mice observed here support the development of regenerative strategies designed to restore telomere integrity.
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            A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis.

            MicroRNAs are well suited to regulate tumor metastasis because of their capacity to coordinately repress numerous target genes, thereby potentially enabling their intervention at multiple steps of the invasion-metastasis cascade. We identify a microRNA exemplifying these attributes, miR-31, whose expression correlates inversely with metastasis in human breast cancer patients. Overexpression of miR-31 in otherwise-aggressive breast tumor cells suppresses metastasis. We deploy a stable microRNA sponge strategy to inhibit miR-31 in vivo; this allows otherwise-nonaggressive breast cancer cells to metastasize. These phenotypes do not involve confounding influences on primary tumor development and are specifically attributable to miR-31-mediated inhibition of several steps of metastasis, including local invasion, extravasation or initial survival at a distant site, and metastatic colonization. Such pleiotropy is achieved via coordinate repression of a cohort of metastasis-promoting genes, including RhoA. Indeed, RhoA re-expression partially reverses miR-31-imposed metastasis suppression. These findings indicate that miR-31 uses multiple mechanisms to oppose metastasis.
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              Senescence-associated exosome release from human prostate cancer cells.

              Males of advanced age represent a rapidly growing population at risk for prostate cancer. In the contemporary setting of earlier detection, a majority of prostate carcinomas are still clinically localized and often treated using radiation therapy. Our recent studies have shown that premature cellular senescence, rather than apoptosis, accounts for most of the clonogenic death induced by clinically relevant doses of irradiation in prostate cancer cells. We show here that this treatment-induced senescence was associated with a significantly increased release of exosome-like microvesicles. In premature senescence, this novel secretory phenotype was dependent on the activation of p53. In addition, the release of exosome-like microvesicles also increased during proliferative senescence in normal human diploid fibroblasts. These data support the hypothesis that senescence, initiated either by telomere attrition (e.g., aging) or DNA damage (e.g., radiotherapy), may induce a p53-dependent increase in the biogenesis of exosome-like vesicles. Ultrastructural analysis and RNA interference-mediated knockdown of Tsg101 provided significant evidence that the additional exosomes released by prematurely senescent prostate cancer cells were principally derived from multivesicular endosomes. Moreover, these exosomes were enriched in B7-H3 protein, a recently identified diagnostic marker for prostate cancer, and an abundance of what has recently been termed "exosomal shuttle RNA." Our findings are consistent with the proposal that exosomes can transfer cargos, with both immunoregulatory potential and genetic information, between cells through a novel mechanism that may be recruited to increase exosome release during accelerated and replicative cellular senescence.
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                Author and article information

                Journal
                Aging Cell
                Aging Cell
                10.1111/(ISSN)1474-9726
                ACEL
                Aging Cell
                John Wiley and Sons Inc. (Hoboken )
                1474-9718
                1474-9726
                04 May 2016
                August 2016
                : 15
                : 4 ( doiID: 10.1111/acel.2016.15.issue-4 )
                : 744-754
                Affiliations
                [ 1 ] Department of BiotechnologyBOKU ‐ University of Natural Resources and Life Sciences Vienna Muthgasse 18 1190 ViennaAustria
                [ 2 ] Ludwig Boltzmann Institute for Experimental and Clinical TraumatologyAUVA Research Center Donaueschingenstrasse 13 A‐1200 ViennaAustria
                [ 3 ]Evercyte GmbH Muthgasse 18 1190 ViennaAustria
                [ 4 ]ACIB Muthgasse 18 1190 ViennaAustria
                [ 5 ] Department of NanoBiotechnology Vienna Institute of BioTechnologyUniversity of Natural Resources and Life Sciences Vienna ViennaAustria
                [ 6 ] Institute of Biomedical Aging ResearchAustrian Academy of Sciences ViennaAustria
                [ 7 ]Children's Cancer Research Institute (CCRI) St. Anna Kinderkrebsforschung ViennaAustria
                [ 8 ] Department of Medicine and Aged Care Royal Melbourne HospitalUniversity of Melbourne MelbourneAustralia
                [ 9 ] Department of Human Movement Sciences MOVE Research Institute AmsterdamVrije Universiteit Amsterdam AmsterdamThe Netherlands
                [ 10 ] Department of public health and center for healthy aginguniversity of Copenhagen Denmark
                [ 11 ] Department of Medicine 2St. Vincent Hospital 1060 ViennaAustria
                [ 12 ] Department of Pathophysiology and Allergy ResearchCenter of Pathophysiology Infectiology and Immunology Medical University of Vienna 1090 ViennaAustria
                [ 13 ]Austrian Cluster for Tissue Regeneration ViennaAustria
                Author notes
                [*] [* ] Correspondence

                Johannes Grillari, Institute of Applied Microbiology, University of Natural Resources and Applied Life Sciences, Vienna, Muthgasse 18, 1190 Vienna. Tel.: +43 1 36006 6230; fax +43 1 3697615; e‐mail: johannes.grillari@ 123456boku.ac.at

                [†]

                Equally contributed to this study.

                Article
                ACEL12484
                10.1111/acel.12484
                4933673
                27146333
                717ca856-53f1-4194-9da3-d581ce0151e5
                © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 21 March 2016
                Page count
                Pages: 11
                Funding
                Funded by: FWF
                Award ID: P24498
                Funded by: GEN‐AU
                Award ID: 820982
                Funded by: ‘Non‐coding RNAs’
                Funded by: FP7 project FRAILOMIC
                Funded by: Herzfelder'sche Familienstiftung
                Funded by: Austrian Federal Ministry of Economy, Family and Youth
                Funded by: National Foundation for Research, Technology and Development
                Funded by: Chanel Research and Technology
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                acel12484
                August 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:25.08.2016

                Cell biology
                aging,mesenchymal stem cells,microrna,osteogenic differentiation,microvesicles,senescence‐associated secretory phenotype

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