Cell Loss during Pseudoislet Formation Hampers Profound Improvements in Islet Lentiviral Transduction Efficacy for Transplantation Purposes
Islet transplantation is a promising treatment in type 1 diabetes, but the need for chronic immunosuppression is a major hurdle to broad applicability. Ex vivo introduction of agents by lentiviral vectors—improving β-cell resistance against immune attack—is an attractive path to pursue. The aim of t...
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Published in | Cell transplantation Vol. 16; no. 5; pp. 527 - 537 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Los Angeles, CA
SAGE Publications
01.05.2007
SAGE Publishing |
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Abstract | Islet transplantation is a promising treatment in type 1 diabetes, but the need for chronic immunosuppression is a major hurdle to broad applicability. Ex vivo introduction of agents by lentiviral vectors—improving β-cell resistance against immune attack—is an attractive path to pursue. The aim of this study was to investigate whether dissociation of islets to single cells prior to viral infection and reaggregation before transplantation would improve viral transduction efficacy without cytotoxicity. This procedure improved transduction efficacy with a LV-pWPT-CMV-EGFP construct from 11.2 ± 4.1% at MOI 50 in whole islets to 80.0 ± 2.8% at MOI 5. Viability (as measured by Hoechst/PI) and functionality (as measured by glucose challenge) remained high. After transplantation, the transfected pseudoislet aggregates remained EGFP positive for more than 90 days and the expression of EGFP colocalized primarily with the insulin-positive β-cells. No increased vulnerability to immune attack was observed in vitro or in vivo. These data demonstrate that dispersion of islets prior to lentiviral transfection and reaggregation prior to transplantation is a highly efficient way to introduce genes of interest into islets for transplantation purposes in vitro and in vivo, but the amount of β-cells needed for normalization of glycemia was more than eightfold higher when using dispersed cell aggregates versus unmanipulated islets. The high price to pay to reach stable and strong transgene expression in islet cells is certainly an important cell loss. |
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AbstractList | Islet transplantation is a promising treatment in type 1 diabetes, but the need for chronic immunosuppression is a major hurdle to broad applicability. Ex vivo introduction of agents by lentiviral vectors—improving β-cell resistance against immune attack—is an attractive path to pursue. The aim of this study was to investigate whether dissociation of islets to single cells prior to viral infection and reaggregation before transplantation would improve viral transduction efficacy without cytotoxicity. This procedure improved transduction efficacy with a LV-pWPT-CMV-EGFP construct from 11.2 ± 4.1% at MOI 50 in whole islets to 80.0 ± 2.8% at MOI 5. Viability (as measured by Hoechst/PI) and functionality (as measured by glucose challenge) remained high. After transplantation, the transfected pseudoislet aggregates remained EGFP positive for more than 90 days and the expression of EGFP colocalized primarily with the insulin-positive β-cells. No increased vulnerability to immune attack was observed in vitro or in vivo. These data demonstrate that dispersion of islets prior to lentiviral transfection and reaggregation prior to transplantation is a highly efficient way to introduce genes of interest into islets for transplantation purposes in vitro and in vivo, but the amount of β-cells needed for normalization of glycemia was more than eightfold higher when using dispersed cell aggregates versus unmanipulated islets. The high price to pay to reach stable and strong transgene expression in islet cells is certainly an important cell loss. Islet transplantation is a promising treatment in type 1 diabetes, but the need for chronic immunosuppression is a major hurdle to broad applicability. Ex vivo introduction of agents by lentiviral vectors-improving beta-cell resistance against immune attack-is an attractive path to pursue. The aim of this study was to investigate whether dissociation of islets to single cells prior to viral infection and reaggregation before transplantation would improve viral transduction efficacy without cytotoxicity. This procedure improved transduction efficacy with a LV-pWPT-CMV-EGFP construct from 11.2 +/- 4.1% at MOI 50 in whole islets to 80.0 +/- 2.8% at MOI 5. Viability (as measured by Hoechst/PI) and functionality (as measured by glucose challenge) remained high. After transplantation, the transfected pseudoislet aggregates remained EGFP positive for more than 90 days and the expression of EGFP colocalized primarily with the insulin-positive beta-cells. No increased vulnerability to immune attack was observed in vitro or in vivo. These data demonstrate that dispersion of islets prior to lentiviral transfection and reaggregation prior to transplantation is a highly efficient way to introduce genes of interest into islets for transplantation purposes in vitro and in vivo, but the amount of beta-cells needed for normalization of glycemia was more than eightfold higher when using dispersed cell aggregates versus unmanipulated islets. The high price to pay to reach stable and strong transgene expression in islet cells is certainly an important cell loss. |
Author | Tiedge, M. Elsner, M. Mathieu, C. Gysemans, C. Eizirik, D. L. Callewaert, H. Cardozo, A. K. |
Author_xml | – sequence: 1 givenname: H. surname: Callewaert fullname: Callewaert, H. – sequence: 2 givenname: C. surname: Gysemans fullname: Gysemans, C. – sequence: 3 givenname: A. K. surname: Cardozo fullname: Cardozo, A. K. – sequence: 4 givenname: M. surname: Elsner fullname: Elsner, M. – sequence: 5 givenname: M. surname: Tiedge fullname: Tiedge, M. – sequence: 6 givenname: D. L. surname: Eizirik fullname: Eizirik, D. L. – sequence: 7 givenname: C. surname: Mathieu fullname: Mathieu, C. email: chantal.mathieu@med.kuleuven.be |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17708342$$D View this record in MEDLINE/PubMed |
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Cites_doi | 10.1007/BF03402037 10.1097/01.TP.0000157275.64874.84 10.1073/pnas.90.18.8392 10.1089/hum.1998.9.18-2717 10.1016/S0041-1345(02)03785-5 10.2337/diabetes.51.7.2148 10.2337/diabetes.48.4.745 10.1111/j.1749-6632.2002.tb02948.x 10.2337/diabetes.50.10.2219 10.1097/01.TP.0000157300.53976.2A 10.1210/en.2003-1070 10.1210/endo-114-6-2205 10.1016/j.trim.2004.04.004 10.2337/diabetes.54.7.2060 10.1016/j.ymthe.2005.02.022 10.2337/diabetes.49.12.1992 10.2337/diabetes.54.suppl_2.S97 10.2337/diabetes.48.11.2107 10.1016/j.ymthe.2005.06.482 10.1210/endo-117-5-2073 10.2337/diabetes.54.8.2396 10.2165/00063030-200216030-00001 10.1128/jvi.69.4.2004-2015.1995 10.1196/annals.1288.007 10.1007/s00125-005-1694-6 10.1016/S0163-7258(98)00020-5 10.1074/jbc.M502213200 10.1038/sj.cgt.7700503 10.1038/sj.gt.3301731 10.1046/j.1365-2249.2000.01300.x 10.1038/sj.gt.3302570 10.1007/s001250100021 10.1128/JVI.72.12.9873-9880.1998 10.2337/diab.40.7.920 |
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Keywords | Islet transplantation Lentiviral vector Pancreatic β-cells Gene therapy Type 1 diabetes Pseudoislet aggregates |
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Snippet | Islet transplantation is a promising treatment in type 1 diabetes, but the need for chronic immunosuppression is a major hurdle to broad applicability. Ex vivo... |
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SubjectTerms | Animals Cell Aggregation - drug effects Cell Death - drug effects Cell Line Cell Separation Cell Survival - drug effects Cytokines - pharmacology Flow Cytometry Humans Insulin - metabolism Insulin Secretion Islets of Langerhans - cytology Islets of Langerhans - drug effects Islets of Langerhans - metabolism Islets of Langerhans Transplantation Lentivirus - genetics Male Mice Rats Rats, Wistar Time Factors Transduction, Genetic Transgenes |
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Title | Cell Loss during Pseudoislet Formation Hampers Profound Improvements in Islet Lentiviral Transduction Efficacy for Transplantation Purposes |
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