title: Role of bone marrow transplantation for correcting hemophilia A in mice.
abstract: To better understand cellular basis of hemophilia, cell types capable of producing FVIII need to be identified. We determined whether bone marrow (BM)-derived cells would produce cells capable of synthesizing and releasing FVIII by transplanting healthy mouse BM into hemophilia A mice. To track donor-derived cells, we used genetic reporters. Use of multiple coagulation assays demonstrated whether FVIII produced by discrete cell populations would correct hemophilia A. We found that animals receiving healthy BM cells survived bleeding challenge with correction of hemophilia, although donor BM-derived hepatocytes or endothelial cells were extremely rare, and these cells did not account for therapeutic benefits. By contrast, donor BM-derived mononuclear and mesenchymal stromal cells were more abundant and expressed FVIII mRNA as well as FVIII protein. Moreover, injection of healthy mouse Kupffer cells (liver macrophage/mononuclear cells), which predominantly originate from BM, or of healthy BM-derived mesenchymal stromal cells, protected hemophilia A mice from bleeding challenge with appearance of FVIII in blood. Therefore, BM transplantation corrected hemophilia A through donor-derived mononuclear cells and mesenchymal stromal cells. These insights into FVIII synthesis and production in alternative cell types will advance studies of pathophysiological mechanisms and therapeutic development in hemophilia A.
authors.affiliation: Department of Pathology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Antonia
authors.initials: A
authors.lastname: Follenzi
authors.forename: Sanj
authors.initials: S
authors.lastname: Raut
authors.forename: Simone
authors.initials: S
authors.lastname: Merlin
authors.forename: Rita
authors.initials: R
authors.lastname: Sarkar
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D042783:Endothelial Cells / Q000166:cytology; D005169:Factor VIII / Q000378:metabolism*; D006467:Hemophilia A / Q000378:metabolism / Q000601:surgery*; D006801:Humans; D007728:Kupffer Cells / Q000637:transplantation; D045164:Mesenchymal Stem Cell Transplantation; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D005169:Factor VIII