Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARp...
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| Veröffentlicht in: | PloS one 2014-11, Vol.9 (11), p.e112746 |
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| creator | Dossena, Marta Bedini, Gloria Rusmini, Paola Giorgetti, Elisa Canazza, Alessandra Tosetti, Valentina Salsano, Ettore Sagnelli, Anna Mariotti, Caterina Gellera, Cinzia Navone, Stefania Elena Marfia, Giovanni Alessandri, Giulio Corsi, Fabio Parati, Eugenio Agostino Pareyson, Davide Poletti, Angelo |
| description | Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA. |
| doi_str_mv | 10.1371/journal.pone.0112746 |
| format | Article |
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Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0112746</identifier><identifier>PMID: 25392924</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adipocytes ; Adipocytes - metabolism ; Adipocytes - pathology ; Adipose Tissue - metabolism ; Adipose Tissue - pathology ; Aged ; Androgen receptors ; Androgens ; Animal models ; Antigens ; Atrophy ; Biocompatibility ; Biology and Life Sciences ; Biomedical materials ; Bone marrow ; Case-Control Studies ; Cell culture ; Cell Differentiation ; Chaperones ; Chondrocytes ; Disease ; Elongation ; Gene Expression Regulation ; Genes ; HSP70 Heat-Shock Proteins - genetics ; HSP70 Heat-Shock Proteins - metabolism ; Hsp70 protein ; Humans ; Inclusion bodies ; Inclusions ; Kennedy's disease ; Laboratories ; Male ; Medicine and Health Sciences ; Mesenchymal stem cells ; Mesenchymal Stem Cells - metabolism ; Mesenchymal Stem Cells - pathology ; Mesenchyme ; Metabolic disorders ; Middle Aged ; Models, Biological ; Molecular modelling ; Muscular Disorders, Atrophic - genetics ; Muscular Disorders, Atrophic - metabolism ; Muscular Disorders, Atrophic - pathology ; Neurobiology ; Neurosciences ; Neurotoxicity ; Nuclear transport ; Osteocytes ; Patients ; Peptides - genetics ; Peptides - metabolism ; Polyglutamine diseases ; Primary Cell Culture ; Proteasome Endopeptidase Complex - metabolism ; Proteasomes ; Proteins ; Receptors, Androgen - genetics ; Receptors, Androgen - metabolism ; Rodents ; Smooth muscle ; Spinal and bulbar muscular atrophy ; Stem cell transplantation ; Stem cells ; Toxicity ; Toxicity testing ; Translocation ; Trinucleotide repeat diseases ; Trinucleotide repeats ; Ubiquitin ; Ubiquitin - genetics ; Ubiquitin - metabolism</subject><ispartof>PloS one, 2014-11, Vol.9 (11), p.e112746</ispartof><rights>2014 Dossena et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Dossena et al 2014 Dossena et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-573b1193a115331c99d81daa17526be217cdaf0168e90d3d9786dfaffbb3b8a73</citedby><cites>FETCH-LOGICAL-c526t-573b1193a115331c99d81daa17526be217cdaf0168e90d3d9786dfaffbb3b8a73</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/PMC4231043/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231043/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25392924$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Pandey, Udai</contributor><creatorcontrib>Dossena, Marta</creatorcontrib><creatorcontrib>Bedini, Gloria</creatorcontrib><creatorcontrib>Rusmini, Paola</creatorcontrib><creatorcontrib>Giorgetti, Elisa</creatorcontrib><creatorcontrib>Canazza, Alessandra</creatorcontrib><creatorcontrib>Tosetti, Valentina</creatorcontrib><creatorcontrib>Salsano, Ettore</creatorcontrib><creatorcontrib>Sagnelli, Anna</creatorcontrib><creatorcontrib>Mariotti, Caterina</creatorcontrib><creatorcontrib>Gellera, Cinzia</creatorcontrib><creatorcontrib>Navone, Stefania Elena</creatorcontrib><creatorcontrib>Marfia, Giovanni</creatorcontrib><creatorcontrib>Alessandri, Giulio</creatorcontrib><creatorcontrib>Corsi, Fabio</creatorcontrib><creatorcontrib>Parati, Eugenio Agostino</creatorcontrib><creatorcontrib>Pareyson, Davide</creatorcontrib><creatorcontrib>Poletti, Angelo</creatorcontrib><title>Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA.</description><subject>Adipocytes</subject><subject>Adipocytes - metabolism</subject><subject>Adipocytes - pathology</subject><subject>Adipose Tissue - metabolism</subject><subject>Adipose Tissue - pathology</subject><subject>Aged</subject><subject>Androgen receptors</subject><subject>Androgens</subject><subject>Animal models</subject><subject>Antigens</subject><subject>Atrophy</subject><subject>Biocompatibility</subject><subject>Biology and Life Sciences</subject><subject>Biomedical materials</subject><subject>Bone marrow</subject><subject>Case-Control Studies</subject><subject>Cell culture</subject><subject>Cell Differentiation</subject><subject>Chaperones</subject><subject>Chondrocytes</subject><subject>Disease</subject><subject>Elongation</subject><subject>Gene Expression Regulation</subject><subject>Genes</subject><subject>HSP70 Heat-Shock Proteins - genetics</subject><subject>HSP70 Heat-Shock Proteins - metabolism</subject><subject>Hsp70 protein</subject><subject>Humans</subject><subject>Inclusion bodies</subject><subject>Inclusions</subject><subject>Kennedy's disease</subject><subject>Laboratories</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Mesenchymal stem cells</subject><subject>Mesenchymal Stem Cells - metabolism</subject><subject>Mesenchymal Stem Cells - pathology</subject><subject>Mesenchyme</subject><subject>Metabolic disorders</subject><subject>Middle Aged</subject><subject>Models, Biological</subject><subject>Molecular modelling</subject><subject>Muscular Disorders, Atrophic - genetics</subject><subject>Muscular Disorders, Atrophic - metabolism</subject><subject>Muscular Disorders, Atrophic - pathology</subject><subject>Neurobiology</subject><subject>Neurosciences</subject><subject>Neurotoxicity</subject><subject>Nuclear transport</subject><subject>Osteocytes</subject><subject>Patients</subject><subject>Peptides - genetics</subject><subject>Peptides - metabolism</subject><subject>Polyglutamine diseases</subject><subject>Primary Cell Culture</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Proteasomes</subject><subject>Proteins</subject><subject>Receptors, Androgen - genetics</subject><subject>Receptors, Androgen - metabolism</subject><subject>Rodents</subject><subject>Smooth muscle</subject><subject>Spinal and bulbar muscular atrophy</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Toxicity</subject><subject>Toxicity testing</subject><subject>Translocation</subject><subject>Trinucleotide repeat diseases</subject><subject>Trinucleotide repeats</subject><subject>Ubiquitin</subject><subject>Ubiquitin - genetics</subject><subject>Ubiquitin - metabolism</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNp1Uktr3DAQFqWlSbb9B6UV9OytnpZ9KZTQJoFAL-1ZjK1R1otsuZKdsP--3q4TkkNBoGFmvgfSR8gHzrZcGv5lH-c0QNiOccAt41wYVb4i57yWoigFk6-f1WfkIuc9Y1pWZfmWnAkta1ELdU7geu5hoOC6MWYsHKbuHh3tMePQ7g49BJon7GmLIWQKy6EDPtA-Ogw0eprHbjFBYXC0mUMDifZzbuewFDClOO4O78gbDyHj-_XekN8_vv-6vC5uf17dXH67LVotyqnQRjZ8MQycayl5W9eu4g6Am2XcoOCmdeAZLyusmZOuNlXpPHjfNLKpwMgN-XTiHUPMdn2dbHkpVK2YWlg35Oa04SLs7Zi6HtLBRujsv0ZMdxbS1LUBLauEBK19KYxWWvnKC2GQOQQQmpmj2tdVbW56dC0OU4LwgvTlZOh29i7eWyUkZ0ouBJ9XghT_zJin_1hWp602xZwT-icFzuwxBo8oe4yBXWOwwD4-d_cEevx3-RfsObFe</recordid><startdate>20141113</startdate><enddate>20141113</enddate><creator>Dossena, Marta</creator><creator>Bedini, Gloria</creator><creator>Rusmini, Paola</creator><creator>Giorgetti, Elisa</creator><creator>Canazza, Alessandra</creator><creator>Tosetti, Valentina</creator><creator>Salsano, Ettore</creator><creator>Sagnelli, Anna</creator><creator>Mariotti, Caterina</creator><creator>Gellera, Cinzia</creator><creator>Navone, Stefania Elena</creator><creator>Marfia, Giovanni</creator><creator>Alessandri, Giulio</creator><creator>Corsi, Fabio</creator><creator>Parati, Eugenio Agostino</creator><creator>Pareyson, Davide</creator><creator>Poletti, Angelo</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20141113</creationdate><title>Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy</title><author>Dossena, Marta ; Bedini, Gloria ; Rusmini, Paola ; Giorgetti, Elisa ; Canazza, Alessandra ; Tosetti, Valentina ; Salsano, Ettore ; Sagnelli, Anna ; Mariotti, Caterina ; Gellera, Cinzia ; Navone, Stefania Elena ; Marfia, Giovanni ; Alessandri, Giulio ; Corsi, Fabio ; Parati, Eugenio Agostino ; Pareyson, Davide ; Poletti, Angelo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-573b1193a115331c99d81daa17526be217cdaf0168e90d3d9786dfaffbb3b8a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adipocytes</topic><topic>Adipocytes - 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metabolism</topic><topic>Mesenchymal Stem Cells - pathology</topic><topic>Mesenchyme</topic><topic>Metabolic disorders</topic><topic>Middle Aged</topic><topic>Models, Biological</topic><topic>Molecular modelling</topic><topic>Muscular Disorders, Atrophic - genetics</topic><topic>Muscular Disorders, Atrophic - metabolism</topic><topic>Muscular Disorders, Atrophic - pathology</topic><topic>Neurobiology</topic><topic>Neurosciences</topic><topic>Neurotoxicity</topic><topic>Nuclear transport</topic><topic>Osteocytes</topic><topic>Patients</topic><topic>Peptides - genetics</topic><topic>Peptides - metabolism</topic><topic>Polyglutamine diseases</topic><topic>Primary Cell Culture</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Proteasomes</topic><topic>Proteins</topic><topic>Receptors, Androgen - genetics</topic><topic>Receptors, Androgen - metabolism</topic><topic>Rodents</topic><topic>Smooth muscle</topic><topic>Spinal and bulbar muscular atrophy</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Toxicity</topic><topic>Toxicity testing</topic><topic>Translocation</topic><topic>Trinucleotide repeat diseases</topic><topic>Trinucleotide repeats</topic><topic>Ubiquitin</topic><topic>Ubiquitin - genetics</topic><topic>Ubiquitin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dossena, Marta</creatorcontrib><creatorcontrib>Bedini, Gloria</creatorcontrib><creatorcontrib>Rusmini, Paola</creatorcontrib><creatorcontrib>Giorgetti, Elisa</creatorcontrib><creatorcontrib>Canazza, Alessandra</creatorcontrib><creatorcontrib>Tosetti, Valentina</creatorcontrib><creatorcontrib>Salsano, Ettore</creatorcontrib><creatorcontrib>Sagnelli, Anna</creatorcontrib><creatorcontrib>Mariotti, Caterina</creatorcontrib><creatorcontrib>Gellera, Cinzia</creatorcontrib><creatorcontrib>Navone, Stefania Elena</creatorcontrib><creatorcontrib>Marfia, Giovanni</creatorcontrib><creatorcontrib>Alessandri, Giulio</creatorcontrib><creatorcontrib>Corsi, Fabio</creatorcontrib><creatorcontrib>Parati, Eugenio Agostino</creatorcontrib><creatorcontrib>Pareyson, Davide</creatorcontrib><creatorcontrib>Poletti, Angelo</creatorcontrib><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>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</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>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dossena, Marta</au><au>Bedini, Gloria</au><au>Rusmini, Paola</au><au>Giorgetti, Elisa</au><au>Canazza, Alessandra</au><au>Tosetti, Valentina</au><au>Salsano, Ettore</au><au>Sagnelli, Anna</au><au>Mariotti, Caterina</au><au>Gellera, Cinzia</au><au>Navone, Stefania Elena</au><au>Marfia, Giovanni</au><au>Alessandri, Giulio</au><au>Corsi, Fabio</au><au>Parati, Eugenio Agostino</au><au>Pareyson, Davide</au><au>Poletti, Angelo</au><au>Pandey, Udai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-11-13</date><risdate>2014</risdate><volume>9</volume><issue>11</issue><spage>e112746</spage><pages>e112746-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is an X-linked CAG/polyglutamine expansion motoneuron disease, in which an elongated polyglutamine tract (polyQ) in the N-terminal androgen receptor (ARpolyQ) confers toxicity to this protein. Typical markers of SBMA disease are ARpolyQ intranuclear inclusions. These are generated after the ARpolyQ binds to its endogenous ligands, which promotes AR release from chaperones, activation and nuclear translocation, but also cell toxicity. The SBMA mouse models developed so far, and used in preclinical studies, all contain an expanded CAG repeat significantly longer than that of SBMA patients. Here, we propose the use of SBMA patients adipose-derived mesenchymal stem cells (MSCs) as a new human in vitro model to study ARpolyQ toxicity. These cells have the advantage to express only ARpolyQ, and not the wild type AR allele. Therefore, we isolated and characterized adipose-derived MSCs from three SBMA patients (ADSC from Kennedy's patients, ADSCK) and three control volunteers (ADSCs). We found that both ADSCs and ADSCKs express mesenchymal antigens, even if only ADSCs can differentiate into the three typical cell lineages (adipocytes, chondrocytes and osteocytes), whereas ADSCKs, from SBMA patients, showed a lower growth potential and differentiated only into adipocyte. Moreover, analysing AR expression on our mesenchymal cultures we found lower levels in all ADSCKs than ADSCs, possibly related to negative pressures exerted by toxic ARpolyQ in ADSCKs. In addition, with proteasome inhibition the ARpolyQ levels increased specifically in ADSCKs, inducing the formation of HSP70 and ubiquitin positive nuclear ARpolyQ inclusions. Considering all of this evidence, SBMA patients adipose-derived MSCs cultures should be considered an innovative in vitro human model to understand the molecular mechanisms of ARpolyQ toxicity and to test novel therapeutic approaches in SBMA.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25392924</pmid><doi>10.1371/journal.pone.0112746</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-11, Vol.9 (11), p.e112746 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1624940415 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adipocytes Adipocytes - metabolism Adipocytes - pathology Adipose Tissue - metabolism Adipose Tissue - pathology Aged Androgen receptors Androgens Animal models Antigens Atrophy Biocompatibility Biology and Life Sciences Biomedical materials Bone marrow Case-Control Studies Cell culture Cell Differentiation Chaperones Chondrocytes Disease Elongation Gene Expression Regulation Genes HSP70 Heat-Shock Proteins - genetics HSP70 Heat-Shock Proteins - metabolism Hsp70 protein Humans Inclusion bodies Inclusions Kennedy's disease Laboratories Male Medicine and Health Sciences Mesenchymal stem cells Mesenchymal Stem Cells - metabolism Mesenchymal Stem Cells - pathology Mesenchyme Metabolic disorders Middle Aged Models, Biological Molecular modelling Muscular Disorders, Atrophic - genetics Muscular Disorders, Atrophic - metabolism Muscular Disorders, Atrophic - pathology Neurobiology Neurosciences Neurotoxicity Nuclear transport Osteocytes Patients Peptides - genetics Peptides - metabolism Polyglutamine diseases Primary Cell Culture Proteasome Endopeptidase Complex - metabolism Proteasomes Proteins Receptors, Androgen - genetics Receptors, Androgen - metabolism Rodents Smooth muscle Spinal and bulbar muscular atrophy Stem cell transplantation Stem cells Toxicity Toxicity testing Translocation Trinucleotide repeat diseases Trinucleotide repeats Ubiquitin Ubiquitin - genetics Ubiquitin - metabolism |
| title | Human adipose-derived mesenchymal stem cells as a new model of spinal and bulbar muscular atrophy |
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