Phenotypic correction of murine hemophilia A using an iPS cell-based therapy

被引:183
作者
Xu, Dan [1 ]
Alipio, Zaida [1 ]
Fink, Louis M. [1 ]
Adcock, Dorothy M. [2 ]
Yang, Jianchang [1 ]
Ward, David C. [1 ]
Ma, Yupo [1 ]
机构
[1] Nevada Canc Inst, Div Lab Med, Las Vegas, NV 89135 USA
[2] Esoterix Coagulat, Englewood, CO 80112 USA
基金
美国国家卫生研究院;
关键词
endothelial cell precursors; Factor VIII; Oct4; Sox2; Klf4; PLURIPOTENT STEM-CELLS; FACTOR-VIII; ENDOTHELIAL-CELLS; IN-VITRO; SOMATIC-CELLS; GENE; INDUCTION; MICE; DIFFERENTIATION; FIBROBLASTS;
D O I
10.1073/pnas.0812090106
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Hemophilia A is caused by mutations within the Factor VIII (FVIII) gene that lead to depleted protein production and inefficient blood clotting. Several attempts at gene therapy have failed for various reasons-including immune rejection. The recent generation of induced pluripotent stem (iPS) cells from somatic cells by the ectopic expression of 3 transcription factors, Oct4, Sox2, and Klf4, provides a means of circumventing the immune rejection barrier. To date, iPS cells appear to be indistinguishable from ES cells and thus provide tremendous therapeutic potential. Here we prepared murine iPS cells from tail-tip fibroblasts and differentiated them to both endothelial cells and endothelial progenitor cells by using the embryoid body differentiation method. These iPS cells express major ES cell markers such as Oct4, Nanog, SSEA-1, alkaline phosphatase, and SALL4. Endothelial/endothelial progenitor cells derived from iPS cells expressed cell-specific markers such as CD31, CD34, and Flk1 and secreted FVIII protein. These iPS-derived cells were injected directly into the liver of irradiated hemophilia A mice. At various times after transplantation (7-90 days) hemophilia A mice and their control mice counterparts were challenged by a tail-clip bleeding assay. Nontransplanted hemophilia A mice died within a few hours, whereas transplanted mice survived for more than 3 months. Plasma FVIII levels increased in transplanted hemophilia A mice during this period to 8% to 12% of wild type and corrected the hemophilia A phenotype. Our studies provide additional evidence that iPS cell therapy may be able to treat human monogenetic disorders in the future.
引用
收藏
页码:808 / 813
页数:6
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