Integrative Multi-omic Profiling of Two Human Decedents Receiving Pig Heart Xenografts Reveals Strong Perturbations in Early Immune-Cell and Cellular Metabolism Responses

• DOI: 10.1101/2023.06.05.543406
• Publication Date: 2023-06-08T15:00:10Z
• Authors: Eloi Schmauch; Brian Piening; Bo Xia; Chenchen Zhu; Jeffrey Stern; Weimin Zhang; Alexa Dowdell; Bao-Li Loza; Maede Mohebnasab; Loren Gragert; Karen Khalil; Brendan Camellato; Michelli Faria de...; Darragh O’Brien; Elaina Weldon; Xiangping Lin; Hui Gao; Larisa Kagermazova; Jacqueline Kim; Alexandre Loupy; Adriana Heguy; Sarah Taylor; Florrie Zhu; Sarah Gao; Divya Gandla; Kriyana Reddy; Andrew Chang; Basil Michael; Lihua Jiang; Ruiqi Jian; Navneet Narula; Suvi Linna-Kuosmanen; Minna Kaikkonen-M...; Marc Lorber; Manolis Kellis; Vasishta Tatapudi; David Ayares; Adam Griesemer; Massimo Mangiola; Harvey Pass; Michael P. Snyder; Robert A. Montgomery; Jef D. Boeke; Brendan J. Keating
• Keywords: Xenotransplantation; Immunosuppression

ABSTRACT Background Recent advances in xenotransplantation living and decedent humans using pig xenografts have laid promising groundwork towards future emergency use first human trials. Major obstacles remain though, including a lack of knowledge the genetic incompatibilities between donors recipients which may led to harmful immune responses against xenograft or dysregulation normal physiology. In 2022 two heart were transplanted into brain-dead decedents with minimized immunosuppression regime, primarily evaluate onset hyper-acute antibody mediated rejection sustained function over 3 days. Methods We performed multi-omic profiling assess dynamic interactions genomes heart-xenografts transplants decedents. To global specific biological changes that correlate immune-related outcomes function, we generated transcriptomic, lipidomic, proteomic metabolomics datasets, across blood tissue samples collected every 6 hours 3-day procedures. Results Single-cell datasets xenograft-decedent models show activation processes. observe scRNA-seq, snRNA-seq geospatial transcriptomic early immune-activation leading pronounced downstream T-cell activity hallmarks (AbMR) and/or ischemia reperfusion injury (IRI) recipient. Using longitudinal multiomic integrative analyses from addition antigen presentation pathway enrichment, also xeno-heart recipient significant cellular metabolism liver damage profound physiological dysfunction whereas, these signals are not present other Conclusions multiomics approaches reveal fundamental insights molecular indicative IRI AbMR decedent, was evident conventional histological evaluations.