Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis
Mesenchymal stem cells (MSCs) promote therapeutic angiogenesis to cure serious vascular disorders. However, their survival period and cytokine-secretory capacity are limited. Although hepatocyte growth factor (HGF) can accelerate the rate of angiogenesis, recombinant HGF is limited because of its ve...
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| Veröffentlicht in: | Molecular therapy 2016-09, Vol.24 (9), p.1644-1654 |
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| creator | Chang, Hyun-Kyung Kim, Pyung-Hwan Cho, Hyun-Min Yum, Soo-Young Choi, Young-Jin Son, YeonSung Lee, DaBin Kang, InSung Kang, Kyung-Sun Jang, Goo Cho, Je-Yoel |
| description | Mesenchymal stem cells (MSCs) promote therapeutic angiogenesis to cure serious vascular disorders. However, their survival period and cytokine-secretory capacity are limited. Although hepatocyte growth factor (HGF) can accelerate the rate of angiogenesis, recombinant HGF is limited because of its very short half-life ( |
| doi_str_mv | 10.1038/mt.2016.120 |
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However, their survival period and cytokine-secretory capacity are limited. Although hepatocyte growth factor (HGF) can accelerate the rate of angiogenesis, recombinant HGF is limited because of its very short half-life (<3–5 minutes). Thus, continuous treatment with HGF is required to obtain an effective therapeutic response. To overcome these limitations, we produced genome-edited MSCs that secreted HGF upon drug-specific induction. The inducible HGF expression cassette was integrated into a safe harbor site in an MSC chromosome using the TALEN system, resulting in the production of TetOn-HGF/human umbilical cord blood-derived (hUCB)-MSCs. Functional assessment of the TetOn-HGF/hUCB-MSCs showed that they had enhanced mobility upon the induction of HGF expression. Moreover, long-term exposure by doxycycline (Dox)-treated TetOn-HGF/hUCB-MSCs enhanced the anti-apoptotic responses of genome-edited MSCs subjected to oxidative stress and improved the tube-formation ability. Furthermore, TetOn-HGF/hUCB-MSCs encapsulated by arginine-glycine-aspartic acid (RGD)-alginate microgel induced to express HGF improved in vivo angiogenesis in a mouse hindlimb ischemia model. This study showed that the inducible HGF-expressing hUCB-MSCs are competent to continuously express and secrete HGF in a controlled manner. Thus, the MSCs that express HGF in an inducible manner are a useful therapeutic modality for the treatment of vascular diseases requiring angiogenesis.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1038/mt.2016.120</identifier><identifier>PMID: 27434585</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Angiogenesis ; Biochemistry ; Cell growth ; Chromosomes ; Efficiency ; Genomes ; Growth factors ; Ischemia ; Original ; Science ; Smooth muscle ; Stem cells ; Umbilical cord ; Veterinary colleges ; Veterinary medicine</subject><ispartof>Molecular therapy, 2016-09, Vol.24 (9), p.1644-1654</ispartof><rights>2016 Official journal of the American Society of Gene & Cell Therapy</rights><rights>Copyright Nature Publishing Group Sep 2016</rights><rights>Copyright © 2016 Official journal of the American Society of Gene & Cell Therapy 2016 Official journal of the American Society of Gene & Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c488t-8cde0e8df0026f934526d392f936f4beb753ff1df83de197b838bd3db07836023</citedby><cites>FETCH-LOGICAL-c488t-8cde0e8df0026f934526d392f936f4beb753ff1df83de197b838bd3db07836023</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/PMC5113099/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5113099/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27434585$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chang, Hyun-Kyung</creatorcontrib><creatorcontrib>Kim, Pyung-Hwan</creatorcontrib><creatorcontrib>Cho, Hyun-Min</creatorcontrib><creatorcontrib>Yum, Soo-Young</creatorcontrib><creatorcontrib>Choi, Young-Jin</creatorcontrib><creatorcontrib>Son, YeonSung</creatorcontrib><creatorcontrib>Lee, DaBin</creatorcontrib><creatorcontrib>Kang, InSung</creatorcontrib><creatorcontrib>Kang, Kyung-Sun</creatorcontrib><creatorcontrib>Jang, Goo</creatorcontrib><creatorcontrib>Cho, Je-Yoel</creatorcontrib><title>Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Mesenchymal stem cells (MSCs) promote therapeutic angiogenesis to cure serious vascular disorders. However, their survival period and cytokine-secretory capacity are limited. Although hepatocyte growth factor (HGF) can accelerate the rate of angiogenesis, recombinant HGF is limited because of its very short half-life (<3–5 minutes). Thus, continuous treatment with HGF is required to obtain an effective therapeutic response. To overcome these limitations, we produced genome-edited MSCs that secreted HGF upon drug-specific induction. The inducible HGF expression cassette was integrated into a safe harbor site in an MSC chromosome using the TALEN system, resulting in the production of TetOn-HGF/human umbilical cord blood-derived (hUCB)-MSCs. Functional assessment of the TetOn-HGF/hUCB-MSCs showed that they had enhanced mobility upon the induction of HGF expression. Moreover, long-term exposure by doxycycline (Dox)-treated TetOn-HGF/hUCB-MSCs enhanced the anti-apoptotic responses of genome-edited MSCs subjected to oxidative stress and improved the tube-formation ability. 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Thus, the MSCs that express HGF in an inducible manner are a useful therapeutic modality for the treatment of vascular diseases requiring angiogenesis.</description><subject>Angiogenesis</subject><subject>Biochemistry</subject><subject>Cell growth</subject><subject>Chromosomes</subject><subject>Efficiency</subject><subject>Genomes</subject><subject>Growth factors</subject><subject>Ischemia</subject><subject>Original</subject><subject>Science</subject><subject>Smooth muscle</subject><subject>Stem cells</subject><subject>Umbilical cord</subject><subject>Veterinary colleges</subject><subject>Veterinary medicine</subject><issn>1525-0016</issn><issn>1525-0024</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>BENPR</sourceid><recordid>eNqNksuLFDEQxhtR3IeevEuDF2HpMY9-pC_COMzOLIwPcPcc0kn1mKWT7CbdA978063ZWQcVD55Sqfrx8dUjy15RMqOEi3dunDFC6xll5El2SitWFYSw8ukxpvVJdpbSLUa0auvn2QlrSl5WojrNflx5M2nbDZCvV5dFAh1htH6bryenfH7jOjtYrYZ8EaLJPwwhmMJAtDsw-cevi5R_iQEF8LezKr-eb5afCgfGqhFTK_DBQb409kESURf2-bnf2rAFD8mmF9mzXg0JXj6-59nN5fJ6sS42n1dXi_mm0KUQYyG0AQLC9Nha3bfontWGtwzDui876JqK9z01veAGaNt0govOcNORRvCaMH6evT_o3k0dGtTgx6gGeRetU_G7DMrKPyvefpPbsJMVpZy0LQq8fRSI4X6CNEpnk4ZhUB7ClCQVrBGC1i37H7RitGEP6Ju_0NswRY-TQIpTzrBfgdTFgdIxpBShP_qmRO6PQLpR7o9A4hEg_fr3Vo_sr60jUB0AwIHvLESZtAWPW7QR9ChNsP8U_gnSzr7v</recordid><startdate>20160901</startdate><enddate>20160901</enddate><creator>Chang, Hyun-Kyung</creator><creator>Kim, Pyung-Hwan</creator><creator>Cho, Hyun-Min</creator><creator>Yum, Soo-Young</creator><creator>Choi, Young-Jin</creator><creator>Son, YeonSung</creator><creator>Lee, DaBin</creator><creator>Kang, InSung</creator><creator>Kang, Kyung-Sun</creator><creator>Jang, Goo</creator><creator>Cho, Je-Yoel</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><general>Nature Publishing Group</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</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>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20160901</creationdate><title>Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis</title><author>Chang, Hyun-Kyung ; 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However, their survival period and cytokine-secretory capacity are limited. Although hepatocyte growth factor (HGF) can accelerate the rate of angiogenesis, recombinant HGF is limited because of its very short half-life (<3–5 minutes). Thus, continuous treatment with HGF is required to obtain an effective therapeutic response. To overcome these limitations, we produced genome-edited MSCs that secreted HGF upon drug-specific induction. The inducible HGF expression cassette was integrated into a safe harbor site in an MSC chromosome using the TALEN system, resulting in the production of TetOn-HGF/human umbilical cord blood-derived (hUCB)-MSCs. Functional assessment of the TetOn-HGF/hUCB-MSCs showed that they had enhanced mobility upon the induction of HGF expression. Moreover, long-term exposure by doxycycline (Dox)-treated TetOn-HGF/hUCB-MSCs enhanced the anti-apoptotic responses of genome-edited MSCs subjected to oxidative stress and improved the tube-formation ability. Furthermore, TetOn-HGF/hUCB-MSCs encapsulated by arginine-glycine-aspartic acid (RGD)-alginate microgel induced to express HGF improved in vivo angiogenesis in a mouse hindlimb ischemia model. This study showed that the inducible HGF-expressing hUCB-MSCs are competent to continuously express and secrete HGF in a controlled manner. Thus, the MSCs that express HGF in an inducible manner are a useful therapeutic modality for the treatment of vascular diseases requiring angiogenesis.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27434585</pmid><doi>10.1038/mt.2016.120</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Angiogenesis Biochemistry Cell growth Chromosomes Efficiency Genomes Growth factors Ischemia Original Science Smooth muscle Stem cells Umbilical cord Veterinary colleges Veterinary medicine |
| title | Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis |
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