Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A
Abstract Hemophilia A (HA) is a bleeding disorder characterized by spontaneous and prolonged hemorrhage. The disease is caused by mutations in the coagulation factor 8 gene (F8) leading to factor VIII (FVIII) deficiency. Since FVIII is primarily produced in endothelial cells (ECs) in a non‐diseased...
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doaj-9b49c5c3207b4640b4388e1e638ad24a2020-11-25T02:59:24ZengWileyStem Cells Translational Medicine2157-65642157-65802020-06-019668669610.1002/sctm.19-0261Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia AMelanie Rose0Kewa Gao1Elizabeth Cortez‐Toledo2Emmanuel Agu3Alicia A. Hyllen4Kelsey Conroy5Guangjin Pan6Jan A. Nolta7Aijun Wang8Ping Zhou9Stem Cell Program, Department of Internal Medicine University of California Davis Medical Center Sacramento CaliforniaDepartment of Surgery University of California Davis Medical Center Sacramento CaliforniaStem Cell Program, Department of Internal Medicine University of California Davis Medical Center Sacramento CaliforniaStem Cell Program, Department of Internal Medicine University of California Davis Medical Center Sacramento CaliforniaStem Cell Program, Department of Internal Medicine University of California Davis Medical Center Sacramento CaliforniaStem Cell Program, Department of Internal Medicine University of California Davis Medical Center Sacramento CaliforniaKey Laboratory of Regenerative Biology Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences Guangzhou ChinaStem Cell Program, Department of Internal Medicine University of California Davis Medical Center Sacramento CaliforniaDepartment of Surgery University of California Davis Medical Center Sacramento CaliforniaStem Cell Program, Department of Internal Medicine University of California Davis Medical Center Sacramento CaliforniaAbstract Hemophilia A (HA) is a bleeding disorder characterized by spontaneous and prolonged hemorrhage. The disease is caused by mutations in the coagulation factor 8 gene (F8) leading to factor VIII (FVIII) deficiency. Since FVIII is primarily produced in endothelial cells (ECs) in a non‐diseased human being, ECs hold great potential for development as a cell therapy for HA. We showed that HA patient‐specific induced pluripotent stem cells (HA‐iPSCs) could provide a renewable supply of ECs. The HA‐iPSC‐derived ECs were transduced with lentiviral vectors to stably express the functional B domain deleted F8 gene, the luciferase gene, and the enhanced green fluorescent protein gene (GFP). When transplanted intramuscularly into neonatal and adult immune deficient mice, the HA‐iPSC‐derived ECs were retained in the animals for at least 10‐16 weeks and maintained their expression of FVIII, GFP, and the endothelial marker CD31, as demonstrated by bioluminescence imaging and immunostaining, respectively. When transplanted into HA mice, these transduced HA‐iPSC‐derived ECs significantly reduced blood loss in a tail‐clip bleeding test and produced therapeutic plasma levels (11.2%‐369.2%) of FVIII. Thus, our studies provide proof‐of‐concept that HA‐iPSC‐derived ECs can serve as a factory to deliver FVIII for the treatment of HA not only in adults but also in newborns.https://doi.org/10.1002/sctm.19-0261cell therapyendothelial cellsFVIIIgene therapyhemophiliainduced pluripotent stem cells (iPSCs) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Melanie Rose Kewa Gao Elizabeth Cortez‐Toledo Emmanuel Agu Alicia A. Hyllen Kelsey Conroy Guangjin Pan Jan A. Nolta Aijun Wang Ping Zhou |
spellingShingle |
Melanie Rose Kewa Gao Elizabeth Cortez‐Toledo Emmanuel Agu Alicia A. Hyllen Kelsey Conroy Guangjin Pan Jan A. Nolta Aijun Wang Ping Zhou Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A Stem Cells Translational Medicine cell therapy endothelial cells FVIII gene therapy hemophilia induced pluripotent stem cells (iPSCs) |
author_facet |
Melanie Rose Kewa Gao Elizabeth Cortez‐Toledo Emmanuel Agu Alicia A. Hyllen Kelsey Conroy Guangjin Pan Jan A. Nolta Aijun Wang Ping Zhou |
author_sort |
Melanie Rose |
title |
Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A |
title_short |
Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A |
title_full |
Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A |
title_fullStr |
Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A |
title_full_unstemmed |
Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A |
title_sort |
endothelial cells derived from patients' induced pluripotent stem cells for sustained factor viii delivery and the treatment of hemophilia a |
publisher |
Wiley |
series |
Stem Cells Translational Medicine |
issn |
2157-6564 2157-6580 |
publishDate |
2020-06-01 |
description |
Abstract Hemophilia A (HA) is a bleeding disorder characterized by spontaneous and prolonged hemorrhage. The disease is caused by mutations in the coagulation factor 8 gene (F8) leading to factor VIII (FVIII) deficiency. Since FVIII is primarily produced in endothelial cells (ECs) in a non‐diseased human being, ECs hold great potential for development as a cell therapy for HA. We showed that HA patient‐specific induced pluripotent stem cells (HA‐iPSCs) could provide a renewable supply of ECs. The HA‐iPSC‐derived ECs were transduced with lentiviral vectors to stably express the functional B domain deleted F8 gene, the luciferase gene, and the enhanced green fluorescent protein gene (GFP). When transplanted intramuscularly into neonatal and adult immune deficient mice, the HA‐iPSC‐derived ECs were retained in the animals for at least 10‐16 weeks and maintained their expression of FVIII, GFP, and the endothelial marker CD31, as demonstrated by bioluminescence imaging and immunostaining, respectively. When transplanted into HA mice, these transduced HA‐iPSC‐derived ECs significantly reduced blood loss in a tail‐clip bleeding test and produced therapeutic plasma levels (11.2%‐369.2%) of FVIII. Thus, our studies provide proof‐of‐concept that HA‐iPSC‐derived ECs can serve as a factory to deliver FVIII for the treatment of HA not only in adults but also in newborns. |
topic |
cell therapy endothelial cells FVIII gene therapy hemophilia induced pluripotent stem cells (iPSCs) |
url |
https://doi.org/10.1002/sctm.19-0261 |
work_keys_str_mv |
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