Open AccessEndothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A
Author(s) -
Rose Melanie,
Gao Kewa,
CortezToledo Elizabeth,
Agu Emmanuel,
Hyllen Alicia A.,
Conroy Kelsey,
Pan Guangjin,
Nolta Jan A.,
Wang Aijun,
Zhou Ping
Publication year - 2020
Publication title -
stem cells translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.781
H-Index - 71
eISSN - 2157-6580
pISSN - 2157-6564
DOI - 10.1002/sctm.19-0261
Subject(s) - induced pluripotent stem cell , genetic enhancement , stem cell , endothelial stem cell , cd31 , medicine , bioluminescence imaging , viral vector , immunology , cancer research , microbiology and biotechnology , biology , transfection , embryonic stem cell , luciferase , cell culture , angiogenesis , gene , recombinant dna , genetics , in vitro
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.