Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion
Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson’s disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a la...
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| Veröffentlicht in: | Scientific reports 2015-07, Vol.5 (1), p.12622-12622, Article 12622 |
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| creator | Tian, Changhai Li, Yuju Huang, Yunlong Wang, Yongxiang Chen, Dapeng Liu, Jinxu Deng, Xiaobei Sun, Lijun Anderson, Kristi Qi, Xinrui Li, Yulong Lee Mosley, R. Chen, Xiangmei Huang, Jian Zheng, Jialin C. |
| description | Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson’s disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astroctyes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment. |
| doi_str_mv | 10.1038/srep12622 |
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Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astroctyes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep12622</identifier><identifier>PMID: 26224135</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/100 ; 13/106 ; 13/109 ; 13/51 ; 14 ; 14/19 ; 38 ; 631/378/368/2430 ; 631/532/2182 ; 631/532/2435 ; 692/699/375/1718 ; Action Potentials - drug effects ; Animals ; Cell Differentiation ; Cell Lineage ; Cell Proliferation - drug effects ; Cells, Cultured ; Dopamine receptors ; Dopaminergic Neurons - cytology ; Dopaminergic Neurons - metabolism ; Doxorubicin - toxicity ; Ectopic expression ; Fibroblasts ; Fibroblasts - cytology ; Fibroblasts - metabolism ; Hepatocyte Nuclear Factor 3-beta - genetics ; Hepatocyte Nuclear Factor 3-beta - metabolism ; Humanities and Social Sciences ; Induced Pluripotent Stem Cells - cytology ; Induced Pluripotent Stem Cells - metabolism ; Induced Pluripotent Stem Cells - transplantation ; LIM-Homeodomain Proteins - genetics ; LIM-Homeodomain Proteins - metabolism ; Male ; Mesencephalon ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Motor task performance ; Movement disorders ; MPTP ; MPTP Poisoning - therapy ; multidisciplinary ; Neostriatum ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Nestin - genetics ; Nestin - metabolism ; Neural stem cells ; Neural Stem Cells - cytology ; Neural Stem Cells - metabolism ; Neurodegeneration ; Neurodegenerative diseases ; Neurogenesis ; Otx Transcription Factors - genetics ; Otx Transcription Factors - metabolism ; Otx2 protein ; Parkinson's disease ; Patch-Clamp Techniques ; POU Domain Factors - genetics ; POU Domain Factors - metabolism ; Proto-Oncogene Proteins c-myc - genetics ; Proto-Oncogene Proteins c-myc - metabolism ; Real-Time Polymerase Chain Reaction ; Rodents ; Science ; Serine Endopeptidases - genetics ; Serine Endopeptidases - metabolism ; SOXB1 Transcription Factors - genetics ; SOXB1 Transcription Factors - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transplantation</subject><ispartof>Scientific reports, 2015-07, Vol.5 (1), p.12622-12622, Article 12622</ispartof><rights>The Author(s) 2015</rights><rights>Copyright Nature Publishing Group Jul 2015</rights><rights>Copyright © 2015, Macmillan Publishers Limited 2015 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c504t-b9066176128e4c104faad883dacae407408207eb4b917365c44e6741dadff3b93</citedby><cites>FETCH-LOGICAL-c504t-b9066176128e4c104faad883dacae407408207eb4b917365c44e6741dadff3b93</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/PMC4519786/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519786/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26224135$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tian, Changhai</creatorcontrib><creatorcontrib>Li, Yuju</creatorcontrib><creatorcontrib>Huang, Yunlong</creatorcontrib><creatorcontrib>Wang, Yongxiang</creatorcontrib><creatorcontrib>Chen, Dapeng</creatorcontrib><creatorcontrib>Liu, Jinxu</creatorcontrib><creatorcontrib>Deng, Xiaobei</creatorcontrib><creatorcontrib>Sun, Lijun</creatorcontrib><creatorcontrib>Anderson, Kristi</creatorcontrib><creatorcontrib>Qi, Xinrui</creatorcontrib><creatorcontrib>Li, Yulong</creatorcontrib><creatorcontrib>Lee Mosley, R.</creatorcontrib><creatorcontrib>Chen, Xiangmei</creatorcontrib><creatorcontrib>Huang, Jian</creatorcontrib><creatorcontrib>Zheng, Jialin C.</creatorcontrib><title>Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson’s disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astroctyes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment.</description><subject>13</subject><subject>13/1</subject><subject>13/100</subject><subject>13/106</subject><subject>13/109</subject><subject>13/51</subject><subject>14</subject><subject>14/19</subject><subject>38</subject><subject>631/378/368/2430</subject><subject>631/532/2182</subject><subject>631/532/2435</subject><subject>692/699/375/1718</subject><subject>Action Potentials - drug effects</subject><subject>Animals</subject><subject>Cell Differentiation</subject><subject>Cell Lineage</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Dopamine receptors</subject><subject>Dopaminergic Neurons - cytology</subject><subject>Dopaminergic Neurons - metabolism</subject><subject>Doxorubicin - toxicity</subject><subject>Ectopic expression</subject><subject>Fibroblasts</subject><subject>Fibroblasts - cytology</subject><subject>Fibroblasts - metabolism</subject><subject>Hepatocyte Nuclear Factor 3-beta - genetics</subject><subject>Hepatocyte Nuclear Factor 3-beta - metabolism</subject><subject>Humanities and Social Sciences</subject><subject>Induced Pluripotent Stem Cells - cytology</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Induced Pluripotent Stem Cells - transplantation</subject><subject>LIM-Homeodomain Proteins - genetics</subject><subject>LIM-Homeodomain Proteins - metabolism</subject><subject>Male</subject><subject>Mesencephalon</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Transgenic</subject><subject>Motor task performance</subject><subject>Movement disorders</subject><subject>MPTP</subject><subject>MPTP Poisoning - therapy</subject><subject>multidisciplinary</subject><subject>Neostriatum</subject><subject>Nerve Tissue Proteins - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Nestin - genetics</subject><subject>Nestin - metabolism</subject><subject>Neural stem cells</subject><subject>Neural Stem Cells - cytology</subject><subject>Neural Stem Cells - metabolism</subject><subject>Neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Neurogenesis</subject><subject>Otx Transcription Factors - genetics</subject><subject>Otx Transcription Factors - metabolism</subject><subject>Otx2 protein</subject><subject>Parkinson's disease</subject><subject>Patch-Clamp Techniques</subject><subject>POU Domain Factors - genetics</subject><subject>POU Domain Factors - metabolism</subject><subject>Proto-Oncogene Proteins c-myc - genetics</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Rodents</subject><subject>Science</subject><subject>Serine Endopeptidases - genetics</subject><subject>Serine Endopeptidases - metabolism</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>SOXB1 Transcription Factors - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transplantation</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkV1LwzAUhoMoTnQX_gEJeKPCNEnTNrkRZH7CREG9Dml6OjPaZibtYP_eyHRMzU1CznPe8_EidEjJOSWJuAge5pRljG2hPUZ4OmIJY9sb7wEahjAj8aRMcip30eAL5zRJ95B5gRpMZxeA76AFrzvrWuwqfO3murHxZ2oNfvZgeh-cD7jyrsGPrg-Ab23hXVHr0AVcLPG1jVSHJzFJTwGPXbsAH6LcAdqpdB1g-H3vo7fbm9fx_WjydPcwvpqMTEp4NyokyTKaZ5QJ4IYSXmldCpGU2mjgJOdEMJJDwQtJ8yRLDeeQ5ZyWuqyqpJDJPrpc6c77ooHSQNt5Xau5t432S-W0Vb8jrX1XU7dQPKUyF1kUOPkW8O6jh9CpxgYDda1biBMrmhOSCZZzEdHjP-jM9b6N4ykqpOQyrjiJ1OmKMt6FaFS1boYS9eWeWrsX2aPN7tfkj1cROFsBIYbaKfiNkv_UPgEWh6Sw</recordid><startdate>20150730</startdate><enddate>20150730</enddate><creator>Tian, Changhai</creator><creator>Li, Yuju</creator><creator>Huang, Yunlong</creator><creator>Wang, Yongxiang</creator><creator>Chen, Dapeng</creator><creator>Liu, Jinxu</creator><creator>Deng, Xiaobei</creator><creator>Sun, Lijun</creator><creator>Anderson, Kristi</creator><creator>Qi, Xinrui</creator><creator>Li, Yulong</creator><creator>Lee Mosley, R.</creator><creator>Chen, Xiangmei</creator><creator>Huang, Jian</creator><creator>Zheng, Jialin C.</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</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>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>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20150730</creationdate><title>Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion</title><author>Tian, Changhai ; Li, Yuju ; Huang, Yunlong ; Wang, Yongxiang ; Chen, Dapeng ; Liu, Jinxu ; Deng, Xiaobei ; Sun, Lijun ; Anderson, Kristi ; Qi, Xinrui ; Li, Yulong ; Lee Mosley, R. ; Chen, Xiangmei ; Huang, Jian ; Zheng, Jialin C.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c504t-b9066176128e4c104faad883dacae407408207eb4b917365c44e6741dadff3b93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>13</topic><topic>13/1</topic><topic>13/100</topic><topic>13/106</topic><topic>13/109</topic><topic>13/51</topic><topic>14</topic><topic>14/19</topic><topic>38</topic><topic>631/378/368/2430</topic><topic>631/532/2182</topic><topic>631/532/2435</topic><topic>692/699/375/1718</topic><topic>Action Potentials - drug effects</topic><topic>Animals</topic><topic>Cell Differentiation</topic><topic>Cell Lineage</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Dopamine receptors</topic><topic>Dopaminergic Neurons - cytology</topic><topic>Dopaminergic Neurons - metabolism</topic><topic>Doxorubicin - toxicity</topic><topic>Ectopic expression</topic><topic>Fibroblasts</topic><topic>Fibroblasts - cytology</topic><topic>Fibroblasts - metabolism</topic><topic>Hepatocyte Nuclear Factor 3-beta - genetics</topic><topic>Hepatocyte Nuclear Factor 3-beta - metabolism</topic><topic>Humanities and Social Sciences</topic><topic>Induced Pluripotent Stem Cells - cytology</topic><topic>Induced Pluripotent Stem Cells - metabolism</topic><topic>Induced Pluripotent Stem Cells - transplantation</topic><topic>LIM-Homeodomain Proteins - genetics</topic><topic>LIM-Homeodomain Proteins - metabolism</topic><topic>Male</topic><topic>Mesencephalon</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Transgenic</topic><topic>Motor task performance</topic><topic>Movement disorders</topic><topic>MPTP</topic><topic>MPTP Poisoning - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tian, Changhai</au><au>Li, Yuju</au><au>Huang, Yunlong</au><au>Wang, Yongxiang</au><au>Chen, Dapeng</au><au>Liu, Jinxu</au><au>Deng, Xiaobei</au><au>Sun, Lijun</au><au>Anderson, Kristi</au><au>Qi, Xinrui</au><au>Li, Yulong</au><au>Lee Mosley, R.</au><au>Chen, Xiangmei</au><au>Huang, Jian</au><au>Zheng, Jialin C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2015-07-30</date><risdate>2015</risdate><volume>5</volume><issue>1</issue><spage>12622</spage><epage>12622</epage><pages>12622-12622</pages><artnum>12622</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson’s disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astroctyes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26224135</pmid><doi>10.1038/srep12622</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/1 13/100 13/106 13/109 13/51 14 14/19 38 631/378/368/2430 631/532/2182 631/532/2435 692/699/375/1718 Action Potentials - drug effects Animals Cell Differentiation Cell Lineage Cell Proliferation - drug effects Cells, Cultured Dopamine receptors Dopaminergic Neurons - cytology Dopaminergic Neurons - metabolism Doxorubicin - toxicity Ectopic expression Fibroblasts Fibroblasts - cytology Fibroblasts - metabolism Hepatocyte Nuclear Factor 3-beta - genetics Hepatocyte Nuclear Factor 3-beta - metabolism Humanities and Social Sciences Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - transplantation LIM-Homeodomain Proteins - genetics LIM-Homeodomain Proteins - metabolism Male Mesencephalon Mice Mice, Inbred C57BL Mice, Transgenic Motor task performance Movement disorders MPTP MPTP Poisoning - therapy multidisciplinary Neostriatum Nerve Tissue Proteins - genetics Nerve Tissue Proteins - metabolism Nestin - genetics Nestin - metabolism Neural stem cells Neural Stem Cells - cytology Neural Stem Cells - metabolism Neurodegeneration Neurodegenerative diseases Neurogenesis Otx Transcription Factors - genetics Otx Transcription Factors - metabolism Otx2 protein Parkinson's disease Patch-Clamp Techniques POU Domain Factors - genetics POU Domain Factors - metabolism Proto-Oncogene Proteins c-myc - genetics Proto-Oncogene Proteins c-myc - metabolism Real-Time Polymerase Chain Reaction Rodents Science Serine Endopeptidases - genetics Serine Endopeptidases - metabolism SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Transcription Factors - genetics Transcription Factors - metabolism Transplantation |
| title | Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T07%3A41%3A21IST&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=Selective%20Generation%20of%20Dopaminergic%20Precursors%20from%20Mouse%20Fibroblasts%20by%20Direct%20Lineage%20Conversion&rft.jtitle=Scientific%20reports&rft.au=Tian,%20Changhai&rft.date=2015-07-30&rft.volume=5&rft.issue=1&rft.spage=12622&rft.epage=12622&rft.pages=12622-12622&rft.artnum=12622&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/srep12622&rft_dat=%3Cproquest_pubme%3E1899492623%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=1899492623&rft_id=info:pmid/26224135&rfr_iscdi=true |