Enhanced collateral growth by double transplantation of gene-nucleofected fibroblasts in ischemic hindlimb of rats
Induction of neovascularization by releasing therapeutic growth factors is a promising application of cell-based gene therapy to treat ischemia-related problems. In the present study, we have developed a new strategy based on nucleofection with alternative solution and cuvette to promote collateral...
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| creator | Zhang, Ziyang Slobodianski, Alex Ito, Wulf D Arnold, Astrid Nehlsen, Jessica Weng, Shaoxiang Lund, Natalie Liu, Jihong Egaña, José-Tomás Lohmeyer, Jörn A Müller, Daniel F Machens, Hans-Günther |
| description | Induction of neovascularization by releasing therapeutic growth factors is a promising application of cell-based gene therapy to treat ischemia-related problems. In the present study, we have developed a new strategy based on nucleofection with alternative solution and cuvette to promote collateral growth and re-establishment of circulation in ischemic limbs using double transplantation of gene nucleofected primary cultures of fibroblasts, which were isolated from rat receiving such therapy.
Rat dermal fibroblasts were nucleofected ex vivo to release bFGF or VEGF165 in a hindlimb ischemia model in vivo. After femoral artery ligation, gene-modified cells were injected intramuscularly. One week post injection, local confined plasmid expression and transient distributions of the plasmids in other organs were detected by quantitative PCR. Quantitative micro-CT analyses showed improvements of vascularization in the ischemic zone (No. of collateral vessels via micro CT: 6.8±2.3 vs. 10.1±2.6; p |
| doi_str_mv | 10.1371/journal.pone.0019192 |
| format | Article |
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Rat dermal fibroblasts were nucleofected ex vivo to release bFGF or VEGF165 in a hindlimb ischemia model in vivo. After femoral artery ligation, gene-modified cells were injected intramuscularly. One week post injection, local confined plasmid expression and transient distributions of the plasmids in other organs were detected by quantitative PCR. Quantitative micro-CT analyses showed improvements of vascularization in the ischemic zone (No. of collateral vessels via micro CT: 6.8±2.3 vs. 10.1±2.6; p<0.05). Moreover, improved collateral proliferation (BrdU incorporation: 0.48±0.05 vs. 0.57±0.05; p<0.05) and increase in blood perfusion (microspheres ratio: gastrocnemius: 0.41±0.10 vs. 0.50±0.11; p<0.05; soleus ratio: soleus: 0.42±0.08 vs. 0.60±0.08; p<0.01) in the lower hindlimb were also observed.
These results demonstrate the feasibility and effectiveness of double transplantation of gene nucleofected primary fibroblasts in producing growth factors and promoting the formation of collateral circulation in ischemic hindlimb, suggesting that isolation and preparation of gene nucleofected cells from individual accepting gene therapy may be an alternative strategy for treating limb ischemia related diseases.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0019192</identifier><identifier>PMID: 21547081</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Angiogenesis ; Animals ; Anticoagulants ; Biotechnology ; Blood vessels ; Cells, Cultured ; Child development ; Clinical trials ; Collateral Circulation - genetics ; Collateral Circulation - physiology ; Computed tomography ; Deoxyribonucleic acid ; DNA ; Drug dosages ; Efficiency ; Endothelial growth factors ; Feasibility studies ; Femoral artery ; Femur ; Fibroblast growth factor 2 ; Fibroblast Growth Factor 2 - genetics ; Fibroblast Growth Factor 2 - metabolism ; Fibroblast growth factors ; Fibroblasts ; Fibroblasts - metabolism ; Fibroblasts - transplantation ; Gene therapy ; Genes ; Growth ; Growth factors ; Hand surgery ; Health aspects ; Hindlimb - pathology ; Hospitals ; Hydrogels ; Ischemia ; Ischemia - therapy ; Male ; Medicine ; Microspheres ; Neovascularization ; Neovascularization, Physiologic - genetics ; Neovascularization, Physiologic - physiology ; Organs ; Perfusion ; Plasmids ; Plasmids - genetics ; Plastic surgery ; Proteins ; Rats ; Rodents ; Skin ; Studies ; Transfection ; Transplantation ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor A - metabolism ; Vascularization ; Vectors (Biology)</subject><ispartof>PloS one, 2011-04, Vol.6 (4), p.e19192-e19192</ispartof><rights>COPYRIGHT 2011 Public Library of Science</rights><rights>2011 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>Zhang et al. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c691t-dd862709f7d4890ec1dc9c51e6bb3f876829e9597737babddee163d2b9505d6c3</citedby><cites>FETCH-LOGICAL-c691t-dd862709f7d4890ec1dc9c51e6bb3f876829e9597737babddee163d2b9505d6c3</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/PMC3081850/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3081850/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21547081$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gaetano, Carlo</contributor><creatorcontrib>Zhang, Ziyang</creatorcontrib><creatorcontrib>Slobodianski, Alex</creatorcontrib><creatorcontrib>Ito, Wulf D</creatorcontrib><creatorcontrib>Arnold, Astrid</creatorcontrib><creatorcontrib>Nehlsen, Jessica</creatorcontrib><creatorcontrib>Weng, Shaoxiang</creatorcontrib><creatorcontrib>Lund, Natalie</creatorcontrib><creatorcontrib>Liu, Jihong</creatorcontrib><creatorcontrib>Egaña, José-Tomás</creatorcontrib><creatorcontrib>Lohmeyer, Jörn A</creatorcontrib><creatorcontrib>Müller, Daniel F</creatorcontrib><creatorcontrib>Machens, Hans-Günther</creatorcontrib><title>Enhanced collateral growth by double transplantation of gene-nucleofected fibroblasts in ischemic hindlimb of rats</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Induction of neovascularization by releasing therapeutic growth factors is a promising application of cell-based gene therapy to treat ischemia-related problems. In the present study, we have developed a new strategy based on nucleofection with alternative solution and cuvette to promote collateral growth and re-establishment of circulation in ischemic limbs using double transplantation of gene nucleofected primary cultures of fibroblasts, which were isolated from rat receiving such therapy.
Rat dermal fibroblasts were nucleofected ex vivo to release bFGF or VEGF165 in a hindlimb ischemia model in vivo. After femoral artery ligation, gene-modified cells were injected intramuscularly. One week post injection, local confined plasmid expression and transient distributions of the plasmids in other organs were detected by quantitative PCR. Quantitative micro-CT analyses showed improvements of vascularization in the ischemic zone (No. of collateral vessels via micro CT: 6.8±2.3 vs. 10.1±2.6; p<0.05). Moreover, improved collateral proliferation (BrdU incorporation: 0.48±0.05 vs. 0.57±0.05; p<0.05) and increase in blood perfusion (microspheres ratio: gastrocnemius: 0.41±0.10 vs. 0.50±0.11; p<0.05; soleus ratio: soleus: 0.42±0.08 vs. 0.60±0.08; p<0.01) in the lower hindlimb were also observed.
These results demonstrate the feasibility and effectiveness of double transplantation of gene nucleofected primary fibroblasts in producing growth factors and promoting the formation of collateral circulation in ischemic hindlimb, suggesting that isolation and preparation of gene nucleofected cells from individual accepting gene therapy may be an alternative strategy for treating limb ischemia related diseases.</description><subject>Angiogenesis</subject><subject>Animals</subject><subject>Anticoagulants</subject><subject>Biotechnology</subject><subject>Blood vessels</subject><subject>Cells, Cultured</subject><subject>Child development</subject><subject>Clinical trials</subject><subject>Collateral Circulation - genetics</subject><subject>Collateral Circulation - physiology</subject><subject>Computed tomography</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Drug dosages</subject><subject>Efficiency</subject><subject>Endothelial growth factors</subject><subject>Feasibility studies</subject><subject>Femoral artery</subject><subject>Femur</subject><subject>Fibroblast growth factor 2</subject><subject>Fibroblast Growth Factor 2 - genetics</subject><subject>Fibroblast Growth Factor 2 - metabolism</subject><subject>Fibroblast growth factors</subject><subject>Fibroblasts</subject><subject>Fibroblasts - metabolism</subject><subject>Fibroblasts - transplantation</subject><subject>Gene therapy</subject><subject>Genes</subject><subject>Growth</subject><subject>Growth factors</subject><subject>Hand surgery</subject><subject>Health aspects</subject><subject>Hindlimb - pathology</subject><subject>Hospitals</subject><subject>Hydrogels</subject><subject>Ischemia</subject><subject>Ischemia - therapy</subject><subject>Male</subject><subject>Medicine</subject><subject>Microspheres</subject><subject>Neovascularization</subject><subject>Neovascularization, Physiologic - genetics</subject><subject>Neovascularization, Physiologic - physiology</subject><subject>Organs</subject><subject>Perfusion</subject><subject>Plasmids</subject><subject>Plasmids - genetics</subject><subject>Plastic surgery</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rodents</subject><subject>Skin</subject><subject>Studies</subject><subject>Transfection</subject><subject>Transplantation</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><subject>Vascularization</subject><subject>Vectors (Biology)</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</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>eNqNk1-P1CAUxRujcdfVb2C0iYnGhxmhtFBeTDabVSfZZBP_vRIKt1MmDIxA1f32Uqe7mTH7YHgoob9zgHO5RfEcoyUmDL_b-DE4aZc772CJEOaYVw-KU8xJtaAVIg8P5ifFkxg3CDWkpfRxcVLhpmaoxadFuHSDdAp0qby1MkGQtlwH_ysNZXdTaj92FsoUpIs7K12SyXhX-r5cg4OFG5UF34NK2aA3XfCdlTHF0rjSRDXA1qhyME5bs-0mVZApPi0e9dJGeDZ_z4pvHy6_XnxaXF1_XF2cXy0U5TgttG5pxRDvma5bjkBhrbhqMNCuI33LaFtx4A1njLBOdloDYEp01fEGNZoqcla83PvurI9ijisKXHFaZw2tM7HaE9rLjdgFs5XhRnhpxN8FH9ZChmTyHUWPOSOIAe0rXiMMLZO1rHpGlaxVy7rs9X7ebey2oBW4HJo9Mj3-48wg1v6nILkObYOywZvZIPgfI8QktjlCyEVx4McoWtrglhM-HfvVP-T9l5uptcznN673eVs1eYrzOqfHCWvaTC3vofLQU-3y0-pNXj8SvD0SZCbB77SWY4xi9eXz_7PX34_Z1wfsANKmIXo7Tu8tHoP1HlTBxxigv8sYIzF1xm0aYuoMMXdGlr04rM-d6LYVyB9j6grJ</recordid><startdate>20110425</startdate><enddate>20110425</enddate><creator>Zhang, Ziyang</creator><creator>Slobodianski, Alex</creator><creator>Ito, Wulf D</creator><creator>Arnold, Astrid</creator><creator>Nehlsen, Jessica</creator><creator>Weng, Shaoxiang</creator><creator>Lund, Natalie</creator><creator>Liu, Jihong</creator><creator>Egaña, José-Tomás</creator><creator>Lohmeyer, Jörn A</creator><creator>Müller, Daniel F</creator><creator>Machens, Hans-Günther</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>IOV</scope><scope>ISR</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>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>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20110425</creationdate><title>Enhanced collateral growth by double transplantation of gene-nucleofected fibroblasts in ischemic hindlimb of rats</title><author>Zhang, Ziyang ; Slobodianski, Alex ; Ito, Wulf D ; Arnold, Astrid ; Nehlsen, Jessica ; Weng, Shaoxiang ; Lund, Natalie ; Liu, Jihong ; Egaña, José-Tomás ; Lohmeyer, Jörn A ; Müller, Daniel F ; Machens, Hans-Günther</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c691t-dd862709f7d4890ec1dc9c51e6bb3f876829e9597737babddee163d2b9505d6c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Angiogenesis</topic><topic>Animals</topic><topic>Anticoagulants</topic><topic>Biotechnology</topic><topic>Blood vessels</topic><topic>Cells, Cultured</topic><topic>Child development</topic><topic>Clinical trials</topic><topic>Collateral Circulation - genetics</topic><topic>Collateral Circulation - physiology</topic><topic>Computed tomography</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>Drug dosages</topic><topic>Efficiency</topic><topic>Endothelial growth factors</topic><topic>Feasibility studies</topic><topic>Femoral artery</topic><topic>Femur</topic><topic>Fibroblast growth factor 2</topic><topic>Fibroblast Growth Factor 2 - genetics</topic><topic>Fibroblast Growth Factor 2 - metabolism</topic><topic>Fibroblast growth factors</topic><topic>Fibroblasts</topic><topic>Fibroblasts - metabolism</topic><topic>Fibroblasts - transplantation</topic><topic>Gene therapy</topic><topic>Genes</topic><topic>Growth</topic><topic>Growth factors</topic><topic>Hand surgery</topic><topic>Health aspects</topic><topic>Hindlimb - pathology</topic><topic>Hospitals</topic><topic>Hydrogels</topic><topic>Ischemia</topic><topic>Ischemia - therapy</topic><topic>Male</topic><topic>Medicine</topic><topic>Microspheres</topic><topic>Neovascularization</topic><topic>Neovascularization, Physiologic - 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Academic</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>Zhang, Ziyang</au><au>Slobodianski, Alex</au><au>Ito, Wulf D</au><au>Arnold, Astrid</au><au>Nehlsen, Jessica</au><au>Weng, Shaoxiang</au><au>Lund, Natalie</au><au>Liu, Jihong</au><au>Egaña, José-Tomás</au><au>Lohmeyer, Jörn A</au><au>Müller, Daniel F</au><au>Machens, Hans-Günther</au><au>Gaetano, Carlo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhanced collateral growth by double transplantation of gene-nucleofected fibroblasts in ischemic hindlimb of rats</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2011-04-25</date><risdate>2011</risdate><volume>6</volume><issue>4</issue><spage>e19192</spage><epage>e19192</epage><pages>e19192-e19192</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Induction of neovascularization by releasing therapeutic growth factors is a promising application of cell-based gene therapy to treat ischemia-related problems. In the present study, we have developed a new strategy based on nucleofection with alternative solution and cuvette to promote collateral growth and re-establishment of circulation in ischemic limbs using double transplantation of gene nucleofected primary cultures of fibroblasts, which were isolated from rat receiving such therapy.
Rat dermal fibroblasts were nucleofected ex vivo to release bFGF or VEGF165 in a hindlimb ischemia model in vivo. After femoral artery ligation, gene-modified cells were injected intramuscularly. One week post injection, local confined plasmid expression and transient distributions of the plasmids in other organs were detected by quantitative PCR. Quantitative micro-CT analyses showed improvements of vascularization in the ischemic zone (No. of collateral vessels via micro CT: 6.8±2.3 vs. 10.1±2.6; p<0.05). Moreover, improved collateral proliferation (BrdU incorporation: 0.48±0.05 vs. 0.57±0.05; p<0.05) and increase in blood perfusion (microspheres ratio: gastrocnemius: 0.41±0.10 vs. 0.50±0.11; p<0.05; soleus ratio: soleus: 0.42±0.08 vs. 0.60±0.08; p<0.01) in the lower hindlimb were also observed.
These results demonstrate the feasibility and effectiveness of double transplantation of gene nucleofected primary fibroblasts in producing growth factors and promoting the formation of collateral circulation in ischemic hindlimb, suggesting that isolation and preparation of gene nucleofected cells from individual accepting gene therapy may be an alternative strategy for treating limb ischemia related diseases.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>21547081</pmid><doi>10.1371/journal.pone.0019192</doi><tpages>e19192</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2011-04, Vol.6 (4), p.e19192-e19192 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1296473764 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Angiogenesis Animals Anticoagulants Biotechnology Blood vessels Cells, Cultured Child development Clinical trials Collateral Circulation - genetics Collateral Circulation - physiology Computed tomography Deoxyribonucleic acid DNA Drug dosages Efficiency Endothelial growth factors Feasibility studies Femoral artery Femur Fibroblast growth factor 2 Fibroblast Growth Factor 2 - genetics Fibroblast Growth Factor 2 - metabolism Fibroblast growth factors Fibroblasts Fibroblasts - metabolism Fibroblasts - transplantation Gene therapy Genes Growth Growth factors Hand surgery Health aspects Hindlimb - pathology Hospitals Hydrogels Ischemia Ischemia - therapy Male Medicine Microspheres Neovascularization Neovascularization, Physiologic - genetics Neovascularization, Physiologic - physiology Organs Perfusion Plasmids Plasmids - genetics Plastic surgery Proteins Rats Rodents Skin Studies Transfection Transplantation Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism Vascularization Vectors (Biology) |
| title | Enhanced collateral growth by double transplantation of gene-nucleofected fibroblasts in ischemic hindlimb of rats |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T00%3A24%3A16IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Enhanced%20collateral%20growth%20by%20double%20transplantation%20of%20gene-nucleofected%20fibroblasts%20in%20ischemic%20hindlimb%20of%20rats&rft.jtitle=PloS%20one&rft.au=Zhang,%20Ziyang&rft.date=2011-04-25&rft.volume=6&rft.issue=4&rft.spage=e19192&rft.epage=e19192&rft.pages=e19192-e19192&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0019192&rft_dat=%3Cgale_plos_%3EA476893758%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1296473764&rft_id=info:pmid/21547081&rft_galeid=A476893758&rft_doaj_id=oai_doaj_org_article_f197307e6f29401e87a4a2f76ca4c87b&rfr_iscdi=true |