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<p>Extracorporeal liver cross-circulation (ELC) using gene-edited porcine liver xenografts offers a potential bridge therapy for liver failure. We previously performed five ELC procedures in four brain-dead human decedents, during which the recipients developed severe thrombocytopenia. The porcine liver xenografts maintained their parenchymal structure, with immune cell infiltration and detectable IgM deposition on endothelial cells. Here, to investigate the underlying host–xenograft interactions, we performed longitudinal proteomic, lipidomic and metabolomic profiling of 64 blood samples, alongside spatial transcriptomics and histology of 25 porcine liver xenograft and 3 native human liver biopsies. Spatial transcriptomic analysis revealed progressive infiltration of human immune cells (predominantly inflammatory macrophages and neutrophils) in the xenografts, concurrent with the loss of porcine Kupffer-like macrophages and T cells. Distinct human and porcine complement dynamics were observed, with suppressed human but elevated porcine complement levels, accompanied by increased levels of porcine acute-phase proteins and coagulation factors. Moreover, multiomics analyses identified candidate cellular and molecular factors associated with thrombocytopenia. Human platelets colocalized with activated porcine endothelial cells, which showed increasing porcine <i>vWF</i> expression over time, as well as with immune cells (primarily macrophages and neutrophils) and hepatocytes in the xenografts. Integrative analyses indicated that ELC procedures provided hepatic support for apolipoprotein synthesis, bilirubin clearance, energy metabolism and detoxification, although circulating lipid levels remained low under anhepatic conditions. Collectively, these findings yield insights into the complex interplay between human and xenograft systems during ELC and inform strategies to improve liver xenograft biocompatibility for clinical translation.</p>

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Longitudinal multiomics profiling of extracorporeal cross-circulation with pig liver xenografts in human decedents

  • 期刊论文

  • 发表日期：

    2026年7月7日

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  • Qian Guo,
  • Chan Wang,
  • Vincent Mauduit,
  • Alexey Stukalov,
  • Maede Mohebnasab,
  • Alex Sagar,
  • Susanna Vikman,
  • Simon H. Williams,
  • Berk Maden,
  • Tal Eitan,
  • Krista Barone,
  • Jennifer D. Motter,
  • Alexa K. Dowdell,
  • Fred L. Robinson,
  • Cyrille Guillot-Tantay,
  • Zasha Zayas,
  • Justin P. Little,
  • Kleio-Maria Verrou,
  • Ángel Gálvez-Merchán,
  • Peng Guo,
  • Kiana Moi,
  • Emmry Stimson,
  • Hui Gao,
  • Diana Argibay,
  • Leah Wu,
  • Austin G. Holmes,
  • Alexandra Q. Bartlett,
  • Dong Xin,
  • Hannah Futeran,
  • Serafim Batzoglou,
  • Shreyas Joshi,
  • Mercy Rophina,
  • Francesca Zanoni,
  • Mohamed A. Elzawahry,
  • John I. Fallon,
  • Syed Hussain Abbas,
  • Kim M. Olthoff,
  • Charles S. Abrams,
  • Sagar Chhangawala,
  • Adam Griesemer,
  • Peter Friend,
  • Asim Siddiqui,
  • Eloi Schmauch,
  • Brian D. Piening,
  • Abraham Shaked,
  • Brendan J. Keating

摘要

Extracorporeal liver cross-circulation (ELC) using gene-edited porcine liver xenografts offers a potential bridge therapy for liver failure. We previously performed five ELC procedures in four brain-dead human decedents, during which the recipients developed severe thrombocytopenia. The porcine liver xenografts maintained their parenchymal structure, with immune cell infiltration and detectable IgM deposition on endothelial cells. Here, to investigate the underlying host–xenograft interactions, we performed longitudinal proteomic, lipidomic and metabolomic profiling of 64 blood samples, alongside spatial transcriptomics and histology of 25 porcine liver xenograft and 3 native human liver biopsies. Spatial transcriptomic analysis revealed progressive infiltration of human immune cells (predominantly inflammatory macrophages and neutrophils) in the xenografts, concurrent with the loss of porcine Kupffer-like macrophages and T cells. Distinct human and porcine complement dynamics were observed, with suppressed human but elevated porcine complement levels, accompanied by increased levels of porcine acute-phase proteins and coagulation factors. Moreover, multiomics analyses identified candidate cellular and molecular factors associated with thrombocytopenia. Human platelets colocalized with activated porcine endothelial cells, which showed increasing porcine vWF expression over time, as well as with immune cells (primarily macrophages and neutrophils) and hepatocytes in the xenografts. Integrative analyses indicated that ELC procedures provided hepatic support for apolipoprotein synthesis, bilirubin clearance, energy metabolism and detoxification, although circulating lipid levels remained low under anhepatic conditions. Collectively, these findings yield insights into the complex interplay between human and xenograft systems during ELC and inform strategies to improve liver xenograft biocompatibility for clinical translation.