Transplanted Endothelial Cells Cure Hemophilia in a Mouse Model

So far, no effective long-term treatment is known.

As part of their strategy to develop a method for curing hemophilia-A permanently, investigators at the Albert Einstein College of Medicine (New York, NY, USA) worked with two populations of genetically engineered mice. The donor group was engineered so that their endothelial cells expressed the gene for green fluorescent protein. This allowed the investigators to trace the donor cells after implantation into the recipient mice, which had been engineered to display the symptoms of hemophilia-A.

The recipient mice were treated with a liver damaging drug before transplantation. This created an environment that encouraged the integration and growth of the transplanted cells. Results published in the February 14, 2008, online edition of The Journal of Clinical Investigation (JCI) revealed that the transplanted cells became integral to the liver structure and reacquired characteristic endothelial morphology. Characterization of transplanted endothelial cells by membrane markers and studies of cellular function, including synthesis and release of coagulation factor VIII, demonstrated that transplanted cells were functionally intact. Further analysis showed that repopulation of the livers of mice that model hemophilia-A with healthy endothelial cells restored plasma factor VIII activity and corrected their bleeding phenotype.

"We have known for three decades that factor VIII is produced in the liver, but precisely where has been controversial,” explained senior author Dr. Sanjeev Gupta, professor of medicine and pathology at the Albert Einstein College of Medicine. "It was assumed that factor VIII was made by the hepatocytes—cells that perform many of the liver's functions and comprise most of its bulk. But our research had suggested that the primary sources were special endothelial cells that line the sinusoids, the liver's blood-filled spaces. We did this study to confirm the role of liver endothelial cells in producing factor VIII and to see if transplanting them from a healthy donor liver could correct hemophilia-A in an animal model.”


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