Hemophilia A, a sex-linked bleeding disorder, is caused by mutations within the genomic sequence of the Factor VIII (FVIII) gene. Mutations of FVIII lead to depleted or reduced protein production, and inefficient clotting. Because hemophilia A is caused by a single gene deficiency, several attempts at gene therapy have been made, including several phase I clinical trials. However, these have all failed for various reasons--including immune rejection. However, with the recent discovery of induced pluripotent stem (iPS) cells the immune rejection barrier can be circumvented. iPS cells can be generated from somatic cells by introducing the ectopic expression of three transcription factors Oct4, Sox2, Klf4 (

Nakagawa et al.,
Nat Biotechnol.
26
:
101
–106,
2008
) To date, iPS cells have been indistinguishable from ES cells, and thus provide tremendous therapeutic potential. In this study, we differentiated iPS cells to endothelial and endothelial progenitor cells using the EB (embryonic bodies) differentiation method. iPS derived endothelial or endothelial progenitor cells express both endothelial or endothelial progenitor cell specific markers, such as CD31, and Flk1, as well as FVIII. These iPS-derived cells were directly injecting into the liver of irradiated hemophilia A model mice. Seven days after transplantation, hemophilia A and control mice were challenged by a tail-clip bleeding assay. Non-transplanted hemophilia A mice died within few hours, while transplanted mice survived for many weeks and more. Plasma FVIII expression in transplanted hemophilia A mice is significantly higher than in non-transplanted hemophilia mice and this elevated expression confers a correction on the hemophilia A phenotype in mice following a tail-clip. Our studies suggest that transplantation of iPS derived endothelial progenitor cells can rescue the phenotype of hemophilia in mouse models and thus potentially suitable for the future development of cell therapy of monogenetic disorders.

Topics:
cell therapy, hemophilia a, idiopathic pneumonia syndrome, phenotype, transplantation, bleeding diathesis, blood coagulation disorders, cd31 antigens, factor viii, hemorrhage

Disclosures: No relevant conflicts of interest to declare.

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2008, The American Society of Hematology
2008
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