Abstract Number: PB2037
Meeting: ISTH 2020 Congress
Background: Hemophilia A cell therapy approaches in pediatric individuals require suitable FVIII-producing cell populations presenting stable engraftment potential. We previously showed that adult-derived FVIII-producing cells, i.e. liver sinusoidal endothelial cells (LSEC) and hematopoietic stem cells (HSC), can be used for the treatment of adult hemophilia A (HA) mice. However, after transplantation in busulfan-conditioned newborn mice, adult LSEC/HSC cannot efficiently engraft, while murine fetal liver (FL) hemato/vascular cells from day 11-13 of gestation (E11-E13) strongly reconstitute the hematopoietic compartment and showed multiorgan endothelial reconstitution potential while secreting FVIII.
Aims: To investigate the engraftment of FL cells in newborn HA mice as a new strategy for the treatment of paediatric HA patients.
Methods: We transplanted FL cells from E11-E13 GFP+ mice into newborn HA mice pre-treated with busulfan (FLE11-E13+BU). Control groups received FLE11-E13 GFP+ cells without busulfan pretreatment (FLE11-E13noBU) or PBS±BU. The engraftment level as well as the FVIII production and activity was assessed in recipients starting from 4 weeks and followed-up for 18 months after transplantation. Moreover, we evaluated the presence of anti-FVIII antibodies/inhibitors in plasma of transplanted mice.
Results: In FLE11-E13+BU group we observed >60% engraftment in peripheral blood with concomitant FVIII activity (up to 16%) which remained stable up to 18 months after transplantation, while engraftment and FVIII activity were lower in absence of preconditioning. Additionally, FLE11-E13+BU group showed the presence of up to 4% of GFP+ LSEC 18 months after transplantation, demonstrating that transplanted FL cells in BU-conditioned newborn mice contributed in reconstituting the hemato/vascular compartment. Mice of FLE11-E13+BU and E13noBU groups did not develop anti-FVIII antibodies, not even after FVIII immunization.
Conclusions: FL cells transplantation may provide a novel and highly promising preclinical model for HA treatment, paving the way for studies aiming at deriving long-term reconstituting “fetal-like” hemato/vascular progenitors from other sources (e.g. iPSC).
To cite this abstract in AMA style:Merlin S, Buzzi S, Akula S, Borroni E, Kalandadze V, Garcia-Leal T, Serrano LJ, Liras A, Sanchez MJ, Follenzi A. Transplantation of Fetal Liver Cells into Newborn Hemophilic Mice for Hemophilia A Cell Therapy [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/transplantation-of-fetal-liver-cells-into-newborn-hemophilic-mice-for-hemophilia-a-cell-therapy/. Accessed January 26, 2022.
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