Abstract Number: OC 50.1
Meeting: ISTH 2022 Congress
Background: We previously showed that adult-derived FVIII-producing cells, i.e. liver sinusoidal endothelial cells (LSECs) and hematopoietic stem cells (HSCs), can be used for the treatment of adult HA mice. However, after transplantation in busulfan-conditioned newborn mice, adult LSEC/HSC cannot efficiently engraft compared to murine fetal liver (FL) hemato/vascular cells from day 11-13 of gestation (E11-E13) that strongly reconstitute the hematopoietic compartment and showed multi-organ endothelial reconstitution potential and FVIII secretion ability.
Aims: To investigate the ability of FL cells in repopulating the hemato/vascular compartment following transplantation in newborn HA mice without preconditioning.
Methods: We transplanted adult BM or FLE11-E13 cells from GFP mice into newborn and adult HA mice pre-treated (+BU) or not (noBU) with busulfan. The engraftment level and FVIII activity was assessed starting from 4w after transplantation and followed-up for 18m. Bleeding phenotype correction was verified by hemarthrosis induction and bleeding assay.
Results: In all BU-conditioned groups we observed long term (18m) stable GFP+ blood engraftment (>60%) with up to 16% FVIII activity following FL and BM cells transplantation. Interestingly, without pre-conditioning we observed lower but stable engraftment (≤12%) and consequent FVIII activity (1-4%) after FL cells transfer, while BM cells did not engraft in noBU mice. Tail bleed challenge and induced hemarthrosis experiments further confirmed the phenotypic correction in all mice receiving FL/BM+BU and in FLnoBU mice. Additionally, we observed an increased survival rate in corrected mice (80%) compared to HA controls (30%). None of the transplanted mice developed anti-FVIII or anti-GFP antibodies.
Conclusion(s): Transplantation of HSCs from adult BM and FL may provide a novel, more stable and highly promising preclinical model for pediatric HA treatment. Our results show FL cells having higher engraftment ability, thus paving the way for studies aimed at maximizing the engraftment and proliferation of donor FVIII-corrective cells while minimizing/avoiding harming pre-conditioning regimens.
To cite this abstract in AMA style:Akula S, merlin S, Cottonaro A, Follenzi A, sanchez M, borroni e, Kalandadze v, garcia leal T, Serrano ramos L, liras a, buzzi s. Transplantation of fetal liver and adult bone marrow cells for phenotypic correction of hemophilia A. [abstract]. https://abstracts.isth.org/abstract/transplantation-of-fetal-liver-and-adult-bone-marrow-cells-for-phenotypic-correction-of-hemophilia-a/. Accessed September 22, 2023.
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