Persistent DNA damage‐induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells
Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells located in various tissues, including the bone marrow. In contrast to terminally differentiated somatic cells, adult stem cells must persist and function throughout life to ensure tissue homeostasis and repair. For this reason, th...
Gespeichert in:
| Veröffentlicht in: | Journal of cellular and molecular medicine 2015-04, Vol.19 (4), p.734-743 |
|---|---|
| Hauptverfasser: | , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 743 |
|---|---|
| container_issue | 4 |
| container_start_page | 734 |
| container_title | Journal of cellular and molecular medicine |
| container_volume | 19 |
| creator | Minieri, Valentina Saviozzi, Silvia Gambarotta, Giovanna Lo Iacono, Marco Accomasso, Lisa Cibrario Rocchietti, Elisa Gallina, Clara Turinetto, Valentina Giachino, Claudia |
| description | Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells located in various tissues, including the bone marrow. In contrast to terminally differentiated somatic cells, adult stem cells must persist and function throughout life to ensure tissue homeostasis and repair. For this reason, they must be equipped with DNA damage responses able to maintain genomic integrity while ensuring their lifelong persistence. Evaluation of hMSC response to genotoxic insults is of great interest considering both their therapeutic potential and their physiological functions. This study aimed to investigate the response of human bone marrow MSCs to the genotoxic agent Actinomycin D (ActD), a well‐known anti‐tumour drug. We report that hMSCs react by undergoing premature senescence driven by a persistent DNA damage response activation, as hallmarked by inhibition of DNA synthesis, p21 and p16 protein expression, marked Senescent Associated β‐galactosidase activity and enlarged γH2AX foci co‐localizing with 53BP1 protein. Senescent hMSCs overexpress several senescence‐associated secretory phenotype (SASP) genes and promote motility of lung tumour and osteosarcoma cell lines in vitro. Our findings disclose a multifaceted consequence of ActD treatment on hMSCs that on the one hand helps to preserve this stem cell pool and prevents damaged cells from undergoing neoplastic transformation, and on the other hand alters their functional effects on the surrounding tissue microenvironment in a way that might worsen their tumour‐promoting behaviour. |
| doi_str_mv | 10.1111/jcmm.12387 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4395188</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1668240580</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5187-ea72ee577e6423fe6c71d52f4f86fb87615e1e3923b388019b00d4488fa80eb63</originalsourceid><addsrcrecordid>eNp9kU1vFCEch0mjsbX10g_QkHgxJlt5mWHgYtJsfU1bPeiZMMyf7mwGWGGmzZ70I_gZ_SSy3bWpHuQCCQ8PP_ghdEzJKS3j1dJ6f0oZl80eOqC1ZLNK8erRbk0ll_voac5LQrigXD1B-6wWVDVcHKDvnyHlPo8QRnx-dYY74801_Prxsw_dZKHDqwTejFMCnCFAthAsYDOM5RgeF4DdFOzYx2AG7OAOzDg6vJi8CbiNAbA3KcVb7KEI7GLtC1nu89jCMOQj9NiZIcOz3XyIvr5982X-fnbx6d2H-dnFzNZUNjMwDQOomwZExbgDYRva1cxVTgrXykbQGihwxXjLpSRUtYR0VSWlM5JAK_gher31rqbWQ1eeMSYz6FXqS7y1jqbXf--EfqGv442uuCoJZBG82AlS_DZBHrXv8-YJJkCcsqZCSFaRWpKCPv8HXcYplR_KmjFFWFEqVaiXW8qmmHMCdx-GEr3pVW961Xe9FvjkYfx79E-RBaBb4LYfYP0flf44v7zcSn8DTVKxaw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2290243999</pqid></control><display><type>article</type><title>Persistent DNA damage‐induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells</title><source>MEDLINE</source><source>Wiley Online Library Open Access</source><source>DOAJ Directory of Open Access Journals</source><source>Wiley Online Library Journals Frontfile Complete</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Minieri, Valentina ; Saviozzi, Silvia ; Gambarotta, Giovanna ; Lo Iacono, Marco ; Accomasso, Lisa ; Cibrario Rocchietti, Elisa ; Gallina, Clara ; Turinetto, Valentina ; Giachino, Claudia</creator><creatorcontrib>Minieri, Valentina ; Saviozzi, Silvia ; Gambarotta, Giovanna ; Lo Iacono, Marco ; Accomasso, Lisa ; Cibrario Rocchietti, Elisa ; Gallina, Clara ; Turinetto, Valentina ; Giachino, Claudia</creatorcontrib><description>Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells located in various tissues, including the bone marrow. In contrast to terminally differentiated somatic cells, adult stem cells must persist and function throughout life to ensure tissue homeostasis and repair. For this reason, they must be equipped with DNA damage responses able to maintain genomic integrity while ensuring their lifelong persistence. Evaluation of hMSC response to genotoxic insults is of great interest considering both their therapeutic potential and their physiological functions. This study aimed to investigate the response of human bone marrow MSCs to the genotoxic agent Actinomycin D (ActD), a well‐known anti‐tumour drug. We report that hMSCs react by undergoing premature senescence driven by a persistent DNA damage response activation, as hallmarked by inhibition of DNA synthesis, p21 and p16 protein expression, marked Senescent Associated β‐galactosidase activity and enlarged γH2AX foci co‐localizing with 53BP1 protein. Senescent hMSCs overexpress several senescence‐associated secretory phenotype (SASP) genes and promote motility of lung tumour and osteosarcoma cell lines in vitro. Our findings disclose a multifaceted consequence of ActD treatment on hMSCs that on the one hand helps to preserve this stem cell pool and prevents damaged cells from undergoing neoplastic transformation, and on the other hand alters their functional effects on the surrounding tissue microenvironment in a way that might worsen their tumour‐promoting behaviour.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/jcmm.12387</identifier><identifier>PMID: 25619736</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Actinomycin ; actinomycin D ; Amino acids ; Antibiotics, Antineoplastic - pharmacology ; Apoptosis ; beta-Galactosidase - metabolism ; Bone cancer ; Bone marrow ; Cancer therapies ; Cell cycle ; Cell differentiation ; Cell Differentiation - drug effects ; Cell Differentiation - genetics ; Cell Line, Tumor ; Cell lines ; Cell Survival - drug effects ; Cell Survival - genetics ; Cells, Cultured ; Cellular Senescence - drug effects ; Cellular Senescence - genetics ; Chemotherapy ; Cyclin-Dependent Kinase Inhibitor p16 - metabolism ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Dactinomycin - pharmacology ; Damage prevention ; Data analysis ; Deoxyribonucleic acid ; DNA ; DNA - genetics ; DNA - metabolism ; DNA biosynthesis ; DNA Damage ; DNA repair ; Galactosidase ; Gene Expression - drug effects ; Genetic transformation ; Genotoxic chemicals ; Genotoxicity ; GTP-binding protein ; Histones - metabolism ; Homeostasis ; Human behavior ; Humans ; Immunoblotting ; Interleukin-6 - genetics ; Interleukin-8 - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; Lung cancer ; Lungs ; Lymphocytes ; mesenchymal stem cell ; Mesenchymal stem cells ; Mesenchymal Stem Cells - drug effects ; Mesenchymal Stem Cells - metabolism ; Mesenchyme ; Microscopy, Confocal ; Original ; Osteosarcoma ; p16 Protein ; Phenotypes ; Physiology ; Protein biosynthesis ; Reverse Transcriptase Polymerase Chain Reaction ; Sarcoma ; Senescence ; senescence‐associated secretory phenotype ; Somatic cells ; Stem cells ; stress‐induced premature senescence ; Tissues ; Tumor cell lines ; Tumor Suppressor p53-Binding Protein 1 ; Tumors ; β-Galactosidase</subject><ispartof>Journal of cellular and molecular medicine, 2015-04, Vol.19 (4), p.734-743</ispartof><rights>2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.</rights><rights>2015. This work is published under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5187-ea72ee577e6423fe6c71d52f4f86fb87615e1e3923b388019b00d4488fa80eb63</citedby><cites>FETCH-LOGICAL-c5187-ea72ee577e6423fe6c71d52f4f86fb87615e1e3923b388019b00d4488fa80eb63</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395188/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395188/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1411,11543,27903,27904,45553,45554,46030,46454,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25619736$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Minieri, Valentina</creatorcontrib><creatorcontrib>Saviozzi, Silvia</creatorcontrib><creatorcontrib>Gambarotta, Giovanna</creatorcontrib><creatorcontrib>Lo Iacono, Marco</creatorcontrib><creatorcontrib>Accomasso, Lisa</creatorcontrib><creatorcontrib>Cibrario Rocchietti, Elisa</creatorcontrib><creatorcontrib>Gallina, Clara</creatorcontrib><creatorcontrib>Turinetto, Valentina</creatorcontrib><creatorcontrib>Giachino, Claudia</creatorcontrib><title>Persistent DNA damage‐induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells</title><title>Journal of cellular and molecular medicine</title><addtitle>J Cell Mol Med</addtitle><description>Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells located in various tissues, including the bone marrow. In contrast to terminally differentiated somatic cells, adult stem cells must persist and function throughout life to ensure tissue homeostasis and repair. For this reason, they must be equipped with DNA damage responses able to maintain genomic integrity while ensuring their lifelong persistence. Evaluation of hMSC response to genotoxic insults is of great interest considering both their therapeutic potential and their physiological functions. This study aimed to investigate the response of human bone marrow MSCs to the genotoxic agent Actinomycin D (ActD), a well‐known anti‐tumour drug. We report that hMSCs react by undergoing premature senescence driven by a persistent DNA damage response activation, as hallmarked by inhibition of DNA synthesis, p21 and p16 protein expression, marked Senescent Associated β‐galactosidase activity and enlarged γH2AX foci co‐localizing with 53BP1 protein. Senescent hMSCs overexpress several senescence‐associated secretory phenotype (SASP) genes and promote motility of lung tumour and osteosarcoma cell lines in vitro. Our findings disclose a multifaceted consequence of ActD treatment on hMSCs that on the one hand helps to preserve this stem cell pool and prevents damaged cells from undergoing neoplastic transformation, and on the other hand alters their functional effects on the surrounding tissue microenvironment in a way that might worsen their tumour‐promoting behaviour.</description><subject>Actinomycin</subject><subject>actinomycin D</subject><subject>Amino acids</subject><subject>Antibiotics, Antineoplastic - pharmacology</subject><subject>Apoptosis</subject><subject>beta-Galactosidase - metabolism</subject><subject>Bone cancer</subject><subject>Bone marrow</subject><subject>Cancer therapies</subject><subject>Cell cycle</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cell Survival - drug effects</subject><subject>Cell Survival - genetics</subject><subject>Cells, Cultured</subject><subject>Cellular Senescence - drug effects</subject><subject>Cellular Senescence - genetics</subject><subject>Chemotherapy</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Dactinomycin - pharmacology</subject><subject>Damage prevention</subject><subject>Data analysis</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA - genetics</subject><subject>DNA - metabolism</subject><subject>DNA biosynthesis</subject><subject>DNA Damage</subject><subject>DNA repair</subject><subject>Galactosidase</subject><subject>Gene Expression - drug effects</subject><subject>Genetic transformation</subject><subject>Genotoxic chemicals</subject><subject>Genotoxicity</subject><subject>GTP-binding protein</subject><subject>Histones - metabolism</subject><subject>Homeostasis</subject><subject>Human behavior</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Interleukin-6 - genetics</subject><subject>Interleukin-8 - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Lung cancer</subject><subject>Lungs</subject><subject>Lymphocytes</subject><subject>mesenchymal stem cell</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stem Cells - drug effects</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mesenchyme</subject><subject>Microscopy, Confocal</subject><subject>Original</subject><subject>Osteosarcoma</subject><subject>p16 Protein</subject><subject>Phenotypes</subject><subject>Physiology</subject><subject>Protein biosynthesis</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>Sarcoma</subject><subject>Senescence</subject><subject>senescence‐associated secretory phenotype</subject><subject>Somatic cells</subject><subject>Stem cells</subject><subject>stress‐induced premature senescence</subject><subject>Tissues</subject><subject>Tumor cell lines</subject><subject>Tumor Suppressor p53-Binding Protein 1</subject><subject>Tumors</subject><subject>β-Galactosidase</subject><issn>1582-1838</issn><issn>1582-4934</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp9kU1vFCEch0mjsbX10g_QkHgxJlt5mWHgYtJsfU1bPeiZMMyf7mwGWGGmzZ70I_gZ_SSy3bWpHuQCCQ8PP_ghdEzJKS3j1dJ6f0oZl80eOqC1ZLNK8erRbk0ll_voac5LQrigXD1B-6wWVDVcHKDvnyHlPo8QRnx-dYY74801_Prxsw_dZKHDqwTejFMCnCFAthAsYDOM5RgeF4DdFOzYx2AG7OAOzDg6vJi8CbiNAbA3KcVb7KEI7GLtC1nu89jCMOQj9NiZIcOz3XyIvr5982X-fnbx6d2H-dnFzNZUNjMwDQOomwZExbgDYRva1cxVTgrXykbQGihwxXjLpSRUtYR0VSWlM5JAK_gher31rqbWQ1eeMSYz6FXqS7y1jqbXf--EfqGv442uuCoJZBG82AlS_DZBHrXv8-YJJkCcsqZCSFaRWpKCPv8HXcYplR_KmjFFWFEqVaiXW8qmmHMCdx-GEr3pVW961Xe9FvjkYfx79E-RBaBb4LYfYP0flf44v7zcSn8DTVKxaw</recordid><startdate>201504</startdate><enddate>201504</enddate><creator>Minieri, Valentina</creator><creator>Saviozzi, Silvia</creator><creator>Gambarotta, Giovanna</creator><creator>Lo Iacono, Marco</creator><creator>Accomasso, Lisa</creator><creator>Cibrario Rocchietti, Elisa</creator><creator>Gallina, Clara</creator><creator>Turinetto, Valentina</creator><creator>Giachino, Claudia</creator><general>John Wiley & Sons, Inc</general><general>BlackWell Publishing Ltd</general><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>201504</creationdate><title>Persistent DNA damage‐induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells</title><author>Minieri, Valentina ; Saviozzi, Silvia ; Gambarotta, Giovanna ; Lo Iacono, Marco ; Accomasso, Lisa ; Cibrario Rocchietti, Elisa ; Gallina, Clara ; Turinetto, Valentina ; Giachino, Claudia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5187-ea72ee577e6423fe6c71d52f4f86fb87615e1e3923b388019b00d4488fa80eb63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Actinomycin</topic><topic>actinomycin D</topic><topic>Amino acids</topic><topic>Antibiotics, Antineoplastic - pharmacology</topic><topic>Apoptosis</topic><topic>beta-Galactosidase - metabolism</topic><topic>Bone cancer</topic><topic>Bone marrow</topic><topic>Cancer therapies</topic><topic>Cell cycle</topic><topic>Cell differentiation</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Differentiation - genetics</topic><topic>Cell Line, Tumor</topic><topic>Cell lines</topic><topic>Cell Survival - drug effects</topic><topic>Cell Survival - genetics</topic><topic>Cells, Cultured</topic><topic>Cellular Senescence - drug effects</topic><topic>Cellular Senescence - genetics</topic><topic>Chemotherapy</topic><topic>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Dactinomycin - pharmacology</topic><topic>Damage prevention</topic><topic>Data analysis</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA - genetics</topic><topic>DNA - metabolism</topic><topic>DNA biosynthesis</topic><topic>DNA Damage</topic><topic>DNA repair</topic><topic>Galactosidase</topic><topic>Gene Expression - drug effects</topic><topic>Genetic transformation</topic><topic>Genotoxic chemicals</topic><topic>Genotoxicity</topic><topic>GTP-binding protein</topic><topic>Histones - metabolism</topic><topic>Homeostasis</topic><topic>Human behavior</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Interleukin-6 - genetics</topic><topic>Interleukin-8 - genetics</topic><topic>Intracellular Signaling Peptides and Proteins - metabolism</topic><topic>Lung cancer</topic><topic>Lungs</topic><topic>Lymphocytes</topic><topic>mesenchymal stem cell</topic><topic>Mesenchymal stem cells</topic><topic>Mesenchymal Stem Cells - drug effects</topic><topic>Mesenchymal Stem Cells - metabolism</topic><topic>Mesenchyme</topic><topic>Microscopy, Confocal</topic><topic>Original</topic><topic>Osteosarcoma</topic><topic>p16 Protein</topic><topic>Phenotypes</topic><topic>Physiology</topic><topic>Protein biosynthesis</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>Sarcoma</topic><topic>Senescence</topic><topic>senescence‐associated secretory phenotype</topic><topic>Somatic cells</topic><topic>Stem cells</topic><topic>stress‐induced premature senescence</topic><topic>Tissues</topic><topic>Tumor cell lines</topic><topic>Tumor Suppressor p53-Binding Protein 1</topic><topic>Tumors</topic><topic>β-Galactosidase</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Minieri, Valentina</creatorcontrib><creatorcontrib>Saviozzi, Silvia</creatorcontrib><creatorcontrib>Gambarotta, Giovanna</creatorcontrib><creatorcontrib>Lo Iacono, Marco</creatorcontrib><creatorcontrib>Accomasso, Lisa</creatorcontrib><creatorcontrib>Cibrario Rocchietti, Elisa</creatorcontrib><creatorcontrib>Gallina, Clara</creatorcontrib><creatorcontrib>Turinetto, Valentina</creatorcontrib><creatorcontrib>Giachino, Claudia</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular and molecular medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Minieri, Valentina</au><au>Saviozzi, Silvia</au><au>Gambarotta, Giovanna</au><au>Lo Iacono, Marco</au><au>Accomasso, Lisa</au><au>Cibrario Rocchietti, Elisa</au><au>Gallina, Clara</au><au>Turinetto, Valentina</au><au>Giachino, Claudia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Persistent DNA damage‐induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells</atitle><jtitle>Journal of cellular and molecular medicine</jtitle><addtitle>J Cell Mol Med</addtitle><date>2015-04</date><risdate>2015</risdate><volume>19</volume><issue>4</issue><spage>734</spage><epage>743</epage><pages>734-743</pages><issn>1582-1838</issn><eissn>1582-4934</eissn><abstract>Human mesenchymal stem cells (hMSCs) are adult multipotent stem cells located in various tissues, including the bone marrow. In contrast to terminally differentiated somatic cells, adult stem cells must persist and function throughout life to ensure tissue homeostasis and repair. For this reason, they must be equipped with DNA damage responses able to maintain genomic integrity while ensuring their lifelong persistence. Evaluation of hMSC response to genotoxic insults is of great interest considering both their therapeutic potential and their physiological functions. This study aimed to investigate the response of human bone marrow MSCs to the genotoxic agent Actinomycin D (ActD), a well‐known anti‐tumour drug. We report that hMSCs react by undergoing premature senescence driven by a persistent DNA damage response activation, as hallmarked by inhibition of DNA synthesis, p21 and p16 protein expression, marked Senescent Associated β‐galactosidase activity and enlarged γH2AX foci co‐localizing with 53BP1 protein. Senescent hMSCs overexpress several senescence‐associated secretory phenotype (SASP) genes and promote motility of lung tumour and osteosarcoma cell lines in vitro. Our findings disclose a multifaceted consequence of ActD treatment on hMSCs that on the one hand helps to preserve this stem cell pool and prevents damaged cells from undergoing neoplastic transformation, and on the other hand alters their functional effects on the surrounding tissue microenvironment in a way that might worsen their tumour‐promoting behaviour.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>25619736</pmid><doi>10.1111/jcmm.12387</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1582-1838 |
| ispartof | Journal of cellular and molecular medicine, 2015-04, Vol.19 (4), p.734-743 |
| issn | 1582-1838 1582-4934 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4395188 |
| source | MEDLINE; Wiley Online Library Open Access; DOAJ Directory of Open Access Journals; Wiley Online Library Journals Frontfile Complete; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Actinomycin actinomycin D Amino acids Antibiotics, Antineoplastic - pharmacology Apoptosis beta-Galactosidase - metabolism Bone cancer Bone marrow Cancer therapies Cell cycle Cell differentiation Cell Differentiation - drug effects Cell Differentiation - genetics Cell Line, Tumor Cell lines Cell Survival - drug effects Cell Survival - genetics Cells, Cultured Cellular Senescence - drug effects Cellular Senescence - genetics Chemotherapy Cyclin-Dependent Kinase Inhibitor p16 - metabolism Cyclin-Dependent Kinase Inhibitor p21 - metabolism Dactinomycin - pharmacology Damage prevention Data analysis Deoxyribonucleic acid DNA DNA - genetics DNA - metabolism DNA biosynthesis DNA Damage DNA repair Galactosidase Gene Expression - drug effects Genetic transformation Genotoxic chemicals Genotoxicity GTP-binding protein Histones - metabolism Homeostasis Human behavior Humans Immunoblotting Interleukin-6 - genetics Interleukin-8 - genetics Intracellular Signaling Peptides and Proteins - metabolism Lung cancer Lungs Lymphocytes mesenchymal stem cell Mesenchymal stem cells Mesenchymal Stem Cells - drug effects Mesenchymal Stem Cells - metabolism Mesenchyme Microscopy, Confocal Original Osteosarcoma p16 Protein Phenotypes Physiology Protein biosynthesis Reverse Transcriptase Polymerase Chain Reaction Sarcoma Senescence senescence‐associated secretory phenotype Somatic cells Stem cells stress‐induced premature senescence Tissues Tumor cell lines Tumor Suppressor p53-Binding Protein 1 Tumors β-Galactosidase |
| title | Persistent DNA damage‐induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T16%3A11%3A11IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Persistent%20DNA%20damage%E2%80%90induced%20premature%20senescence%20alters%20the%20functional%20features%20of%20human%20bone%20marrow%20mesenchymal%20stem%20cells&rft.jtitle=Journal%20of%20cellular%20and%20molecular%20medicine&rft.au=Minieri,%20Valentina&rft.date=2015-04&rft.volume=19&rft.issue=4&rft.spage=734&rft.epage=743&rft.pages=734-743&rft.issn=1582-1838&rft.eissn=1582-4934&rft_id=info:doi/10.1111/jcmm.12387&rft_dat=%3Cproquest_pubme%3E1668240580%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2290243999&rft_id=info:pmid/25619736&rfr_iscdi=true |