Patient-Specific iPSC-Derived Endothelial Cells Provide Long-Term Phenotypic Correction of Hemophilia A

Publication date: Available online 8 November 2018Source: Stem Cell ReportsAuthor(s): 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 FollenziSummaryWe 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 a...
Source: Stem Cell Reports - Category: Stem Cells Source Type: research