The therapeutic effect of bone marrow–derived liver cells in the phenotypic correction of murine hemophilia A

Yadav, Neelam; Kanjirakkuzhiyil, Sumod; Kumar, Suresh; Jain, Manish; Halder, Ashutosh; Saxena, Renu; Mukhopadhyay, Asok

doi:10.1182/blood-2009-02-202788

Cited by 39 publications

(33 citation statements)

References 52 publications

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“…41,42 In those studies, injection of BM-derived cells was thought to produce efficient engraftment of transplanted cells in liver, including generation of hepatocytes and LSECs in sufficient numbers to indefinitely correct FVIII deficiency. However, we observed neither hepatocytes nor LSECs to any significance in BM transplantation studies, despite extensive BM chimerism in lethally irradiated mice, which argued against the possibility of permanent correction of hemophilia by peripheral injection of BM-derived cells.…”

Section: Discussionmentioning

confidence: 99%

Role of bone marrow transplantation for correcting hemophilia A in mice

Follenzi

Raut

Merlin

et al. 2012

Blood

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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. IntroductionHemophilia A is characterized by inability to clot blood because of FVIII gene mutations and deficiency of this coagulation factor. 1 The potential for cell and gene therapy in hemophilia A is highly attractive because even small amounts of FVIII may substantially decrease bleeding risk. This requires sound knowledge of cell types capable of replacing FVIII, especially within proximity of von Willebrand factor (vWF), which protects FVIII from degradation. 2 However, the cell-type origin of FVIII has been controversial. 3 Correction of hemophilia after orthotopic liver transplantation (OLT) but not after kidney transplantation, despite FVIII mRNA expression in both organs, 3,4 indicated that liver was a major site for FVIII production. Recently, the cell transplantation approach established that of various liver cell types, liver sinusoidal endothelial cells (LSECs) replaced FVIII in hemophilia mice. 5,6 Nonetheless, extrahepatic organs probably contributed in FVIII production, as indicated by FVIII synthesis in spleen, lungs, or pancreatic islets. [6][7][8] This was in agreement with lack of plasma FVIII deficiency after OLT with donor liver from dogs or people with hemophilia A because such donor liver cells would not have synthesized or secreted FVIII. 9,10 Therefore, whether nonendothelial cells, and cells in extrahepatic organs, could also produce FVIII was not excluded. For instance, macrophages, which originate in bone marrow (BM), and contained FVIII mRNA, 11 could be such a candidate. Although FVIII was cloned from T cells, 12 and transplantation of lymphatic tissue was thought to correct hemophilia in dogs, 13 whether lymphocytes did express FVIII was uncertain, because correction of hemophilia by transplanted organs (eg, spleen) included other cell types. 7,14,15 Because BM cells may generate multiple lineages, the potential of BM-derived cells in FVIII production seemed relevant to us. Previously, BM transplantation studies in hemophilia A, 40 years ago, were limited to just 3 dogs and 2 persons. [16][17][18][19] BM transplantation in hemophilia dogs was carefully performed, although there were limitations, such as suboptimal allograft tolerance, lack of studies showing engraftment and generation of various BM cell types, absence of FVIII expression analysis in donor BM-derived cells,...

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Section: Discussionmentioning

confidence: 99%

Role of bone marrow transplantation for correcting hemophilia A in mice

Follenzi

Raut

Merlin

et al. 2012

Blood

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“…22 Recently, bone marrow (BM) transplantation was demonstrated to correct the bleeding phenotype in HA mice, in part through donor-derived monocytes/macrophages and mesenchymal stromal cells. 23,24 Further investigations into the role of hematopoietic cells in FVIII expression are, therefore, appropriate. December 29, 2014.…”

Section: Introductionmentioning

confidence: 99%

Extrahepatic sources of factor VIII potentially contribute to the coagulation cascade correcting the bleeding phenotype of mice with hemophilia A

et al. 2015

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“…Studies at the National Institute of Immunology using an animal model has shown that bone marrow-derived allogeneic stem cell could be used to improve bleeding in haemophiliac mice with regeneration and differentiation of allogenic stem cells into liver cells, this study also could be taken further to see if it can reach clinical trial stage [17]. Allogenic liver transplantation does cure haemophilia [18], though I am not advocating it yet seeing the vast improvement in the expertise technique and outcome in live donor transplantation in our country, who knows that some research will not take place in this direction.…”

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confidence: 99%