Academic Journal
Patient-Specific iPSC-Derived Endothelial Cells Provide Long-Term Phenotypic Correction of Hemophilia A
| Title: | Patient-Specific iPSC-Derived Endothelial Cells Provide Long-Term Phenotypic Correction of Hemophilia A |
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| Authors: | Cristina Olgasi, Maria Talmon, Simone Merlin, Alessia Cucci, Yvonne Richaud-Patin, Gabriella Ranaldo, Donato Colangelo, Federica Di Scipio, Giovanni N. Berta, Chiara Borsotti, Federica Valeri, Francesco Faraldi, Maria Prat, Maria Messina, Piercarla Schinco, Angelo Lombardo, Angel Raya, Antonia Follenzi |
| Source: | Stem Cell Reports, Vol 11, Iss 6, Pp 1391-1406 (2018) |
| Publisher Information: | Elsevier, 2018. |
| Publication Year: | 2018 |
| Collection: | LCC:Medicine (General) LCC:Biology (General) |
| Subject Terms: | Medicine (General), R5-920, Biology (General), QH301-705.5 |
| More Details: | Summary: We generated patient-specific disease-free induced pluripotent stem cells (iPSCs) from peripheral blood CD34+ cells and differentiated them into functional endothelial cells (ECs) secreting factor VIII (FVIII) for gene and cell therapy approaches to cure hemophilia A (HA), an X-linked bleeding disorder caused by F8 mutations. iPSCs were transduced with a lentiviral vector carrying FVIII transgene driven by an endothelial-specific promoter (VEC) and differentiated into bona fide ECs using an optimized protocol. FVIII-expressing ECs were intraportally transplanted in monocrotaline-conditioned non-obese diabetic (NOD) severe combined immune-deficient (scid)-IL2rγ null HA mice generating a chimeric liver with functional human ECs. Transplanted cells engrafted and proliferated in the liver along sinusoids, in the long term showed stable therapeutic FVIII activity (6%). These results demonstrate that the hemophilic phenotype can be rescued by transplantation of ECs derived from HA FVIII-corrected iPSCs, confirming the feasibility of cell-reprogramming strategy in patient-derived cells as an approach for HA gene and cell therapy. : Follenzi and colleagues show that endothelial cells can be obtained starting from blood CD34+ cells of both healthy and hemophilic donors passing through iPSC generation. During the differentiation process the cells can be genetically modified by LV to express FVIII; corrected endothelial cells secrete FVIII in vitro and ameliorate the hemophilic phenotype in a mouse model of the disease. Keywords: hemophilia A, induced pluripotent stem cells (iPSCs), endothelial cells, cell and gene therapy, FVIII, chimeric vasculature, lentiviral vectors |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2213-6711 |
| Relation: | http://www.sciencedirect.com/science/article/pii/S2213671118304351; https://doaj.org/toc/2213-6711 |
| DOI: | 10.1016/j.stemcr.2018.10.012 |
| Access URL: | https://doaj.org/article/8867c765fe344630b78a3afcd6aa23de |
| Accession Number: | edsdoj.8867c765fe344630b78a3afcd6aa23de |
| Database: | Directory of Open Access Journals |
| ISSN: | 22136711 |
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| DOI: | 10.1016/j.stemcr.2018.10.012 |
| Published in: | Stem Cell Reports |
| Language: | English |