In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase
Human embryonic stem cells (hESCs) provide a novel source of hematopoietic and other cell populations suitable for gene therapy applications. Preclinical studies to evaluate engraftment of hESC-derived hematopoietic cells transplanted into immunodeficient mice demonstrate only limited repopulation....
Gespeichert in:
| Veröffentlicht in: | Gene therapy 2010-02, Vol.17 (2), p.238-249 |
|---|---|
| Hauptverfasser: | , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 249 |
|---|---|
| container_issue | 2 |
| container_start_page | 238 |
| container_title | Gene therapy |
| container_volume | 17 |
| creator | Gori, J L Tian, X Swanson, D Gunther, R Shultz, L D McIvor, R S Kaufman, D S |
| description | Human embryonic stem cells (hESCs) provide a novel source of hematopoietic and other cell populations suitable for gene therapy applications. Preclinical studies to evaluate engraftment of hESC-derived hematopoietic cells transplanted into immunodeficient mice demonstrate only limited repopulation. Expression of a drug-resistance gene, such as Tyr22-dihydrofolate reductase (Tyr22-DHFR), coupled to methotrexate (MTX) chemotherapy has the potential to selectively increase the engraftment of gene-modified, hESC-derived cells in mouse xenografts. Here, we describe the generation of Tyr22-DHFR–GFP-expressing hESCs that maintain pluripotency, produce teratomas and can differentiate into MTXr-hemato-endothelial cells. We demonstrate that MTX administered to nonobese diabetic/severe combined immunodeficient/IL-2Rγc
null
(NSG) mice after injection of Tyr22-DHFR-hESC-derived cells significantly increases human CD34
+
and CD45
+
cell engraftment in the bone marrow (BM) and peripheral blood of transplanted MTX-treated mice. These results demonstrate that MTX treatment supports selective, long-term engraftment of Tyr22-DHFR cells
in vivo
, and provides a novel approach for combined human cell and gene therapy. |
| doi_str_mv | 10.1038/gt.2009.131 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2820606</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A219449555</galeid><sourcerecordid>A219449555</sourcerecordid><originalsourceid>FETCH-LOGICAL-c626t-726b19273f6df5d60b76b8f4eae348200d0006428fd6a0fbdc56169aa2708f033</originalsourceid><addsrcrecordid>eNp1kt2L1DAUxYso7uzqk-8SFBdEOyZpm7YvwrL4MbAg-PEc0vSmzdImY5IOM__9ps6wsyP6FHLvj3NzTm6SvCB4SXBWfejCkmJcL0lGHiULkpcsLXJGHycLXLM6LQmtzpJz728xxnlZ0afJGakrWmeELZLNyqCN3ljkYQAZtDXIKtRPozAIxsbtrNES-QAjkjAMaQtOb6D9c_EItmsH3mvToRFCb4ODrQiQxqL2QZiAWt3vWmeVHWIdOWgnGYSHZ8kTJQYPzw_nRfLr86ef11_Tm29fVtdXN6lklIW0pKwhNS0zxVpVtAw3JWsqlYOALK-i6zZ6YjmtVMsEVk0rC0ZYLQQtcaVwll0kH_e666kZoZVgghMDXzs9CrfjVmh-2jG6553dcBrVGWZR4PIg4OzvCXzgo_azeWHATp7TmDorMhzB13-Bt3ZyJprjlOU5K2pSVJF69V-KVGV8dk2PUp0YgGujYq5CznP5FSV1ntdFUUTq7QklrQmwDZ2YvOerH99P2csHbA9iCL23wzT_tz8F3-1B6az3DtR9VATzedt4F_i8bTz6jvTLh-ke2cN6ReDNARBeikE5YaT29xylGasyMo99v-d8bJkO3DGWf829A9Za6p0</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>218727092</pqid></control><display><type>article</type><title>In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase</title><source>MEDLINE</source><source>Free E-Journal (出版社公開部分のみ）</source><source>SpringerLink (Online service)</source><creator>Gori, J L ; Tian, X ; Swanson, D ; Gunther, R ; Shultz, L D ; McIvor, R S ; Kaufman, D S</creator><creatorcontrib>Gori, J L ; Tian, X ; Swanson, D ; Gunther, R ; Shultz, L D ; McIvor, R S ; Kaufman, D S</creatorcontrib><description>Human embryonic stem cells (hESCs) provide a novel source of hematopoietic and other cell populations suitable for gene therapy applications. Preclinical studies to evaluate engraftment of hESC-derived hematopoietic cells transplanted into immunodeficient mice demonstrate only limited repopulation. Expression of a drug-resistance gene, such as Tyr22-dihydrofolate reductase (Tyr22-DHFR), coupled to methotrexate (MTX) chemotherapy has the potential to selectively increase the engraftment of gene-modified, hESC-derived cells in mouse xenografts. Here, we describe the generation of Tyr22-DHFR–GFP-expressing hESCs that maintain pluripotency, produce teratomas and can differentiate into MTXr-hemato-endothelial cells. We demonstrate that MTX administered to nonobese diabetic/severe combined immunodeficient/IL-2Rγc
null
(NSG) mice after injection of Tyr22-DHFR-hESC-derived cells significantly increases human CD34
+
and CD45
+
cell engraftment in the bone marrow (BM) and peripheral blood of transplanted MTX-treated mice. These results demonstrate that MTX treatment supports selective, long-term engraftment of Tyr22-DHFR cells
in vivo
, and provides a novel approach for combined human cell and gene therapy.</description><identifier>ISSN: 0969-7128</identifier><identifier>EISSN: 1476-5462</identifier><identifier>DOI: 10.1038/gt.2009.131</identifier><identifier>PMID: 19829316</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Animals ; Applied cell therapy and gene therapy ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Biotechnology ; Bone Marrow ; Bone marrow transplantation ; CD34 antigen ; CD45 antigen ; Cell Biology ; Cell Differentiation ; Cell Line ; Chemotherapy ; Diabetes mellitus ; Dihydrofolate reductase ; Drug Resistance ; Embryo cells ; Embryonic stem cells ; Embryonic Stem Cells - metabolism ; Embryos ; Endothelial cells ; Fundamental and applied biological sciences. Psychology ; Gene Expression ; Gene Therapy ; Genetic aspects ; Genetic Therapy - methods ; Graft Survival ; Health aspects ; Health. Pharmaceutical industry ; Human Genetics ; Humans ; Immunodeficiency ; Industrial applications and implications. Economical aspects ; Interleukin 2 receptors ; Medical sciences ; Methotrexate ; Methotrexate - pharmacology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Nanotechnology ; original-article ; Peripheral blood ; Physiological aspects ; Pluripotency ; Rodents ; Stem cell transplantation ; Stem Cell Transplantation - methods ; Stem cells ; Teratoma - genetics ; Tetrahydrofolate Dehydrogenase - genetics ; Tetrahydrofolate Dehydrogenase - metabolism ; Transfusions. Complications. Transfusion reactions. Cell and gene therapy ; Xenografts</subject><ispartof>Gene therapy, 2010-02, Vol.17 (2), p.238-249</ispartof><rights>Macmillan Publishers Limited 2010</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2010 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Feb 2010</rights><rights>Macmillan Publishers Limited 2010.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c626t-726b19273f6df5d60b76b8f4eae348200d0006428fd6a0fbdc56169aa2708f033</citedby><cites>FETCH-LOGICAL-c626t-726b19273f6df5d60b76b8f4eae348200d0006428fd6a0fbdc56169aa2708f033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/gt.2009.131$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/gt.2009.131$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22368315$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19829316$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gori, J L</creatorcontrib><creatorcontrib>Tian, X</creatorcontrib><creatorcontrib>Swanson, D</creatorcontrib><creatorcontrib>Gunther, R</creatorcontrib><creatorcontrib>Shultz, L D</creatorcontrib><creatorcontrib>McIvor, R S</creatorcontrib><creatorcontrib>Kaufman, D S</creatorcontrib><title>In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase</title><title>Gene therapy</title><addtitle>Gene Ther</addtitle><addtitle>Gene Ther</addtitle><description>Human embryonic stem cells (hESCs) provide a novel source of hematopoietic and other cell populations suitable for gene therapy applications. Preclinical studies to evaluate engraftment of hESC-derived hematopoietic cells transplanted into immunodeficient mice demonstrate only limited repopulation. Expression of a drug-resistance gene, such as Tyr22-dihydrofolate reductase (Tyr22-DHFR), coupled to methotrexate (MTX) chemotherapy has the potential to selectively increase the engraftment of gene-modified, hESC-derived cells in mouse xenografts. Here, we describe the generation of Tyr22-DHFR–GFP-expressing hESCs that maintain pluripotency, produce teratomas and can differentiate into MTXr-hemato-endothelial cells. We demonstrate that MTX administered to nonobese diabetic/severe combined immunodeficient/IL-2Rγc
null
(NSG) mice after injection of Tyr22-DHFR-hESC-derived cells significantly increases human CD34
+
and CD45
+
cell engraftment in the bone marrow (BM) and peripheral blood of transplanted MTX-treated mice. These results demonstrate that MTX treatment supports selective, long-term engraftment of Tyr22-DHFR cells
in vivo
, and provides a novel approach for combined human cell and gene therapy.</description><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Animals</subject><subject>Applied cell therapy and gene therapy</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Biotechnology</subject><subject>Bone Marrow</subject><subject>Bone marrow transplantation</subject><subject>CD34 antigen</subject><subject>CD45 antigen</subject><subject>Cell Biology</subject><subject>Cell Differentiation</subject><subject>Cell Line</subject><subject>Chemotherapy</subject><subject>Diabetes mellitus</subject><subject>Dihydrofolate reductase</subject><subject>Drug Resistance</subject><subject>Embryo cells</subject><subject>Embryonic stem cells</subject><subject>Embryonic Stem Cells - metabolism</subject><subject>Embryos</subject><subject>Endothelial cells</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Genetic aspects</subject><subject>Genetic Therapy - methods</subject><subject>Graft Survival</subject><subject>Health aspects</subject><subject>Health. Pharmaceutical industry</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunodeficiency</subject><subject>Industrial applications and implications. Economical aspects</subject><subject>Interleukin 2 receptors</subject><subject>Medical sciences</subject><subject>Methotrexate</subject><subject>Methotrexate - pharmacology</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Nanotechnology</subject><subject>original-article</subject><subject>Peripheral blood</subject><subject>Physiological aspects</subject><subject>Pluripotency</subject><subject>Rodents</subject><subject>Stem cell transplantation</subject><subject>Stem Cell Transplantation - methods</subject><subject>Stem cells</subject><subject>Teratoma - genetics</subject><subject>Tetrahydrofolate Dehydrogenase - genetics</subject><subject>Tetrahydrofolate Dehydrogenase - metabolism</subject><subject>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</subject><subject>Xenografts</subject><issn>0969-7128</issn><issn>1476-5462</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kt2L1DAUxYso7uzqk-8SFBdEOyZpm7YvwrL4MbAg-PEc0vSmzdImY5IOM__9ps6wsyP6FHLvj3NzTm6SvCB4SXBWfejCkmJcL0lGHiULkpcsLXJGHycLXLM6LQmtzpJz728xxnlZ0afJGakrWmeELZLNyqCN3ljkYQAZtDXIKtRPozAIxsbtrNES-QAjkjAMaQtOb6D9c_EItmsH3mvToRFCb4ODrQiQxqL2QZiAWt3vWmeVHWIdOWgnGYSHZ8kTJQYPzw_nRfLr86ef11_Tm29fVtdXN6lklIW0pKwhNS0zxVpVtAw3JWsqlYOALK-i6zZ6YjmtVMsEVk0rC0ZYLQQtcaVwll0kH_e666kZoZVgghMDXzs9CrfjVmh-2jG6553dcBrVGWZR4PIg4OzvCXzgo_azeWHATp7TmDorMhzB13-Bt3ZyJprjlOU5K2pSVJF69V-KVGV8dk2PUp0YgGujYq5CznP5FSV1ntdFUUTq7QklrQmwDZ2YvOerH99P2csHbA9iCL23wzT_tz8F3-1B6az3DtR9VATzedt4F_i8bTz6jvTLh-ke2cN6ReDNARBeikE5YaT29xylGasyMo99v-d8bJkO3DGWf829A9Za6p0</recordid><startdate>20100201</startdate><enddate>20100201</enddate><creator>Gori, J L</creator><creator>Tian, X</creator><creator>Swanson, D</creator><creator>Gunther, R</creator><creator>Shultz, L D</creator><creator>McIvor, R S</creator><creator>Kaufman, D S</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>IQODW</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>ISR</scope><scope>3V.</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</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>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>PRINS</scope><scope>7QO</scope><scope>5PM</scope></search><sort><creationdate>20100201</creationdate><title>In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase</title><author>Gori, J L ; Tian, X ; Swanson, D ; Gunther, R ; Shultz, L D ; McIvor, R S ; Kaufman, D S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c626t-726b19273f6df5d60b76b8f4eae348200d0006428fd6a0fbdc56169aa2708f033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Animals</topic><topic>Applied cell therapy and gene therapy</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Biotechnology</topic><topic>Bone Marrow</topic><topic>Bone marrow transplantation</topic><topic>CD34 antigen</topic><topic>CD45 antigen</topic><topic>Cell Biology</topic><topic>Cell Differentiation</topic><topic>Cell Line</topic><topic>Chemotherapy</topic><topic>Diabetes mellitus</topic><topic>Dihydrofolate reductase</topic><topic>Drug Resistance</topic><topic>Embryo cells</topic><topic>Embryonic stem cells</topic><topic>Embryonic Stem Cells - metabolism</topic><topic>Embryos</topic><topic>Endothelial cells</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene Expression</topic><topic>Gene Therapy</topic><topic>Genetic aspects</topic><topic>Genetic Therapy - methods</topic><topic>Graft Survival</topic><topic>Health aspects</topic><topic>Health. Pharmaceutical industry</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunodeficiency</topic><topic>Industrial applications and implications. Economical aspects</topic><topic>Interleukin 2 receptors</topic><topic>Medical sciences</topic><topic>Methotrexate</topic><topic>Methotrexate - pharmacology</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Nanotechnology</topic><topic>original-article</topic><topic>Peripheral blood</topic><topic>Physiological aspects</topic><topic>Pluripotency</topic><topic>Rodents</topic><topic>Stem cell transplantation</topic><topic>Stem Cell Transplantation - methods</topic><topic>Stem cells</topic><topic>Teratoma - genetics</topic><topic>Tetrahydrofolate Dehydrogenase - genetics</topic><topic>Tetrahydrofolate Dehydrogenase - metabolism</topic><topic>Transfusions. Complications. Transfusion reactions. Cell and gene therapy</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gori, J L</creatorcontrib><creatorcontrib>Tian, X</creatorcontrib><creatorcontrib>Swanson, D</creatorcontrib><creatorcontrib>Gunther, R</creatorcontrib><creatorcontrib>Shultz, L D</creatorcontrib><creatorcontrib>McIvor, R S</creatorcontrib><creatorcontrib>Kaufman, D S</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest_Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest Public Health Database</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>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</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>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>ProQuest_Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>ProQuest Central China</collection><collection>Biotechnology Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gori, J L</au><au>Tian, X</au><au>Swanson, D</au><au>Gunther, R</au><au>Shultz, L D</au><au>McIvor, R S</au><au>Kaufman, D S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase</atitle><jtitle>Gene therapy</jtitle><stitle>Gene Ther</stitle><addtitle>Gene Ther</addtitle><date>2010-02-01</date><risdate>2010</risdate><volume>17</volume><issue>2</issue><spage>238</spage><epage>249</epage><pages>238-249</pages><issn>0969-7128</issn><eissn>1476-5462</eissn><abstract>Human embryonic stem cells (hESCs) provide a novel source of hematopoietic and other cell populations suitable for gene therapy applications. Preclinical studies to evaluate engraftment of hESC-derived hematopoietic cells transplanted into immunodeficient mice demonstrate only limited repopulation. Expression of a drug-resistance gene, such as Tyr22-dihydrofolate reductase (Tyr22-DHFR), coupled to methotrexate (MTX) chemotherapy has the potential to selectively increase the engraftment of gene-modified, hESC-derived cells in mouse xenografts. Here, we describe the generation of Tyr22-DHFR–GFP-expressing hESCs that maintain pluripotency, produce teratomas and can differentiate into MTXr-hemato-endothelial cells. We demonstrate that MTX administered to nonobese diabetic/severe combined immunodeficient/IL-2Rγc
null
(NSG) mice after injection of Tyr22-DHFR-hESC-derived cells significantly increases human CD34
+
and CD45
+
cell engraftment in the bone marrow (BM) and peripheral blood of transplanted MTX-treated mice. These results demonstrate that MTX treatment supports selective, long-term engraftment of Tyr22-DHFR cells
in vivo
, and provides a novel approach for combined human cell and gene therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>19829316</pmid><doi>10.1038/gt.2009.131</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0969-7128 |
| ispartof | Gene therapy, 2010-02, Vol.17 (2), p.238-249 |
| issn | 0969-7128 1476-5462 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2820606 |
| source | MEDLINE; Free E-Journal (出版社公開部分のみ）; SpringerLink (Online service) |
| subjects | Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Applied cell therapy and gene therapy Biological and medical sciences Biomedical and Life Sciences Biomedicine Biotechnology Bone Marrow Bone marrow transplantation CD34 antigen CD45 antigen Cell Biology Cell Differentiation Cell Line Chemotherapy Diabetes mellitus Dihydrofolate reductase Drug Resistance Embryo cells Embryonic stem cells Embryonic Stem Cells - metabolism Embryos Endothelial cells Fundamental and applied biological sciences. Psychology Gene Expression Gene Therapy Genetic aspects Genetic Therapy - methods Graft Survival Health aspects Health. Pharmaceutical industry Human Genetics Humans Immunodeficiency Industrial applications and implications. Economical aspects Interleukin 2 receptors Medical sciences Methotrexate Methotrexate - pharmacology Mice Mice, Inbred NOD Mice, SCID Nanotechnology original-article Peripheral blood Physiological aspects Pluripotency Rodents Stem cell transplantation Stem Cell Transplantation - methods Stem cells Teratoma - genetics Tetrahydrofolate Dehydrogenase - genetics Tetrahydrofolate Dehydrogenase - metabolism Transfusions. Complications. Transfusion reactions. Cell and gene therapy Xenografts |
| title | In vivo selection of human embryonic stem cell-derived cells expressing methotrexate-resistant dihydrofolate reductase |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-14T15%3A54%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=In%20vivo%20selection%20of%20human%20embryonic%20stem%20cell-derived%20cells%20expressing%20methotrexate-resistant%20dihydrofolate%20reductase&rft.jtitle=Gene%20therapy&rft.au=Gori,%20J%20L&rft.date=2010-02-01&rft.volume=17&rft.issue=2&rft.spage=238&rft.epage=249&rft.pages=238-249&rft.issn=0969-7128&rft.eissn=1476-5462&rft_id=info:doi/10.1038/gt.2009.131&rft_dat=%3Cgale_pubme%3EA219449555%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=218727092&rft_id=info:pmid/19829316&rft_galeid=A219449555&rfr_iscdi=true |