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iPSC-derived Endothelial Cells - A Promising new Approach for Hemophilia A Treatment

Review of "Endothelial Cells Derived from Patients' Induced Pluripotent Stem Cells for Sustained FVIII Delivery and the Treatment of Hemophilia A" from STEM CELLS Translational Medicine by Stuart P. Atkinson 

Mutations in the F8 gene that lead to a deficiency of clotting factor VIII (FVIII) cause hemophilia A, an X‐linked recessive bleeding disorder that can lead to disability and even death due to spontaneous or injury‐caused prolonged bleeding. Factor replacement by repeated infusions of recombinant FVIII protein suffers from multiple challenges, including the risk of infection, inconvenience, expense, and frequent bleeding episodes due to fluctuations of infused factor levels.

Endothelial cells normally express and post-translationally modify FVIII [1, 2], and, therefore, treatment with this cell type has emerged as an alternative therapeutic approach to hemophilia A. As limited availability hinders the clinical application of endothelial cells derived from natural sources, the implementation of cells derived from patient-specific induced pluripotent stem cells (iPSCs) [3, 4] may represent a relevant strategy moving forward.

Now, in a recent STEM CELLS Translational Medicine article, researchers led by Aijun Wang and Ping Zhou (University of California Davis, Sacramento, CA, USA) reported their encouraging findings regarding the implementation of endothelial cells differentiated from patient-specific iPSCs as FVIII delivery vehicles in the treatment of hemophilia A in an animal model [5]. 

Rose et al. first efficiently differentiated previously characterized iPSC lines derived from hemophilia A patients [6, 7] into endothelial cells using a previously established protocol [4] and then transduced cells with lentiviral vectors to stably express a functional F8 gene. The efficacy of this treatment in patients during early life is a priority, given the genetic cause of  Hemophilia A, and the authors established that transduced endothelial cells stably engrafted and survived for between 10 and 16 weeks following their intramuscular transplantation into wild type neonatal and adult immunodeficient mice. Furthermore, transduced endothelial cells maintained their expression of the FVIII protein and the CD31 endothelial cell marker, while the study noted a lack of signs of endothelial cell expansion or teratoma formation. Finally, the authors assessed the potential of the transduced endothelial cells to treat the symptoms of hemophilia A by transplanting them into neonatal hemophilia A model mice; encouragingly, the team observed significantly reduced blood loss in a tail‐clip bleeding test and therapeutically relevant plasma levels of FVIII.

These findings provide evidence for the implementation of endothelial cells derived from patient-specific iPSCs as FVIII delivery vehicles for the treatment of hemophilia A in both adults and newborns and the authors next hope to move to larger animal models to optimize their approach and fully evaluate efficacy and safety.

For more on how endothelial cells derived from patient-specific iPSCs may represent the future of hemophilia A treatment, stay tuned to the Stem Cells Portal!



  1. Everett LA, Cleuren ACA, Khoriaty RN, et al., Murine Coagulation Factor VIII is Synthesized in Endothelial Cells. Blood 2014;123:3697-3705.
  2. Fahs SA, Hille MT, Shi Q, et al., A Conditional Knockout Mouse Model Reveals Endothelial Cells as the Principal and Possibly Exclusive Source of Plasma Factor VIII. Blood 2014;123:3706-3713.
  3. Patsch C, Challet-Meylan L, Thoma EC, et al., Generation of Vascular Endothelial and Smooth Muscle Cells from Human Pluripotent Stem Cells. Nature Cell Biology 2015;17:994-1003.
  4. Harding A, Cortez-Toledo E, Magner NL, et al., Highly Efficient Differentiation of Endothelial Cells from Pluripotent Stem Cells Requires the MAPK and the PI3K Pathways. STEM CELLS 2017;35:909-919.
  5. Rose M, Gao K, Cortez-Toledo E, et al., Endothelial cells derived from patients' induced pluripotent stem cells for sustained factor VIII delivery and the treatment of hemophilia A. STEM CELLS Translational Medicine 2020;9:686-696.
  6. Jia B, Chen S, Zhao Z, et al., Modeling of Hemophilia A Using Patient-specific Induced Pluripotent Stem Cells Derived from Urine Cells. Life Sciences 2014;108:22-29.
  7. Xue Y, Cai X, Wang L, et al., Generating a Non-Integrating Human Induced Pluripotent Stem Cell Bank from Urine-Derived Cells. PLOS ONE 2013;8:e70573.