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The mesenchymal stem cells derived from transgenic mice carrying human coagulation factor VIII can correct phenotype in hemophilia A mice. | LitMetric

The mesenchymal stem cells derived from transgenic mice carrying human coagulation factor VIII can correct phenotype in hemophilia A mice.

J Genet Genomics

Shanghai Institute of Medical Genetics, Children's Hospital of Shanghai, Shanghai Jiao Tong University School of Medicine, Shanghai 200040, China; Key Laboratory of Embryo Molecular Biology, Ministry of Health & Shanghai Key Laboratory of Embryo and Reproduction Engineering, Shanghai 200040, China. Electronic address:

Published: December 2013

AI Article Synopsis

  • Hemophilia A (HA) is a genetic bleeding disorder caused by a deficiency in factor VIII, and prior research indicated that modified mesenchymal stem cells (MSCs) could help correct this condition in animal models.
  • This study explored a new gene therapy approach by creating a transgenic mouse line that expresses a modified form of human FVIII (hFVIIIBD) and subsequently isolating hFVIIIBD-MSCs for transplantation into HA mice.
  • The results showed that the transplanted MSCs led to significant increases in FVIII levels and improved blood clotting times in HA mice, indicating successful phenotypic correction.

Article Abstract

Hemophilia A (HA) is an inherited X-linked recessive bleeding disorder caused by coagulant factor VIII (FVIII) deficiency. Previous studies showed that introduction of mesenchymal stem cells (MSCs) modified by FVIII-expressing retrovirus may result in phenotypic correction of HA animals. This study aimed at the investigation of an alternative gene therapy strategy that may lead to sustained FVIII transgene expression in HA mice. B-domain-deleted human FVIII (hFVIIIBD) vector was microinjected into single-cell embryos of wild-type mice to generate a transgenic mouse line, from which hFVIIIBD-MSCs were isolated, followed by transplantation into HA mice. RT-PCR and real-time PCR analysis demonstrated the expression of hFVIIIBD in multi-organs of recipient HA mice. Immunohistochemistry showed the presence of hFVIIIBD positive staining in multi-organs of recipient HA mice. ELISA indicated that plasma hFVIIIBD level in recipient mice reached its peak (77 ng/mL) at the 3rd week after implantation, and achieved sustained expression during the 5-week observation period. Plasma FVIII activities of recipient HA mice increased from 0% to 32% after hFVIIIBD-MSCs transplantation. APTT (activated partial thromboplastin time) value decreased in hFVIIIBD-MSCs transplanted HA mice compared with untreated HA mice (45.5 s vs. 91.3 s). Our study demonstrated an effective phenotypic correction in HA mice using genetically modified MSCs from hFVIIIBD transgenic mice.

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Source
http://dx.doi.org/10.1016/j.jgg.2013.11.002DOI Listing

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