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Generation of vascular chimerism within donor organs.

ABSTRACT: Whole organ perfusion decellularization has been proposed as a promising method to generate non-immunogenic organs from allogeneic and xenogeneic donors. However, the ability to recellularize organ scaffolds with multiple patient-specific cells in a spatially controlled manner remains challenging. Here, we propose that replacing donor endothelial cells alone, while keeping the rest of the organ viable and functional, is more technically feasible, and may offer a significant shortcut in the efforts to engineer transplantable organs. Vascular decellularization was achieved ex vivo, under controlled machine perfusion conditions, in various rat and porcine organs, including the kidneys, liver, lungs, heart, aorta, hind limbs, and pancreas. In addition, vascular decellularization of selected organs was performed in situ, within the donor body, achieving better control over the perfusion process. Human placenta-derived endothelial progenitor cells (EPCs) were used as immunologically-acceptable human cells to repopulate the luminal surface of de-endothelialized aorta (in vitro), kidneys, lungs and hind limbs (ex vivo). This study provides evidence that artificially generating vascular chimerism is feasible and could potentially pave the way for crossing the immunological barrier to xenotransplantation, as well as reducing the immunological burden of allogeneic grafts.

SUBMITTER: Cohen S

PROVIDER: S-EPMC8238957 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine's metabolite, 9-?-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4(+) and CD8(+) cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients.Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine-F-ara-A area under the curve (AUC) and the ratio of circulating CD4(+) and CD8(+) cells (CD4(+)/CD8(+) ratio) after fludarabine administration-in 102 patients; F-ara-ATP accumulation rate in enriched CD4(+) and CD8(+) cells was evaluated in 36 and 34 patients, respectively.Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8(+) cells). Circulating CD8(+) cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was a poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4(+) (R (2) = 0.01) and CD8(+) cells (R (2) = 0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality).Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers are not associated with clinical outcomes in fludarabine/TBI-conditioned patients.

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Generation of vascular chimerism within donor organs.

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