The search for the origin of factor VIII synthesis and its impact on therapeutic strategies for hemophilia A
Year: 2015
Type: editorial
Abstract: A ctivated factor IX and its cofactor, activated factor VIII, are critical for the proteolytic activation of factor X. Inherited deficiencies of these factors cause the bleeding disorders hemophilia B and hemophilia A, respectively.The development of recombinant expression systems for factor VIII, following the isolation of the F8 gene, 1 was a major advance that significantly improved the treatment of hemophilia A. Currently, several approaches to alter the hemophilia A phenotype by cell and/or gene therapy are under development.Although it has been well-recognized from a series of experiments in hemophilia A dogs and human liver transplantation that there are both hepatic and extrahepatic sources of factor VIII, 2,3 the identity of the specific cells responsible for the level of circulating factor VIII has long remained an unresolved issue.[4][5][6] In this issue of the journal, Zanolini and colleagues provide new insight into both the hepatic and hematopoietic-derived cellular origin of circulating factor VIII. 7 Using multiple sources of hematopoietic cells (bonemarrow derived or cord blood CD34 + cells) from humans, they identified (by both mRNA and immunofluorescence staining of protein) that monocytes and monocyte-derived macrophages are the main cells of the hematopoietic system responsible for factor VIII. Monocytes and monocyte-derived macrophages in peripheral blood also expressed factor VIII mRNA and protein, but at lower levels.Furthermore, upon differentiation of human CD34 + cells to megakaryocytes, mRNA and protein staining also showed factor VIII expression in the differentiated cells.However, the relative contribution of factor VIII from these hematopoietic-derived sources to the total circulating levels remains to be determined.Similar findings in humans were also obtained in mouse models in the current study as well as in a previously published study by the same group.8 Notably, in a series of experiments in hemophilia A mice, injection of isolated CD11 + human monocytes resulted in a transient increase in the circulating levels of factor VIII; the protein was biologically active, as demonstrated by the improved survival of animals upon hemostatic challenge to the macrocirculation (tail clip assay).Furthermore, hemophilia A mice that received cord bloodderived CD34 + cells from wild-type donors following total body irradiation experienced a dose-dependent elevation of factor VIII levels and improvement of the bleeding phenotype upon vascular injury.Recently, three studies addressed the cellular origin of factor VIII synthesis in the liver.[4][5][6] The overall conclusion was that liver sinusoid endothelial cells (LSEC), not hepatocytes, are the main cellular source of hepatic factor VIII. Here, in a unique set of experiments, the authors demonstrated that transplant of non-parenchymal cells (a mix of Küpffer cells and LSEC), improved circulating factor VIII levels, but infusion of isolated hepatocyte did not.These findings support the emerging understanding that both murine and human Dangerous liaisons: cooperation between Pbx3, Meis1 and Hoxa9 in leukemia
Source: Haematologica
Author: V. R. Arruda
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,157
OpenAlex ID: W2158374766