Integrative multi-omics profiling in human decedents receiving pig heart xenografts

Eloi Schmauch, Brian Piening, Maedeh Mohebnasab, Bo Xia, Chenchen Zhu, Jeffrey Stern, Weimin Zhang, Alexa K. Dowdell, Jacqueline I. Kim, David Andrijevic, Karen Khalil, Ian S. Jaffe, Bao Li Loza, Loren Gragert, Brendan R. Camellato, Michelli F. Oliveira, Darragh P. O’Brien, Han M. Chen, Elaina Weldon, Hui GaoDivya Gandla, Andrew Chang, Riyana Bhatt, Sarah Gao, Xiangping Lin, Kriyana P. Reddy, Larisa Kagermazova, Alawi H. Habara, Sophie Widawsky, Feng Xia Liang, Joseph Sall, Alexandre Loupy, Adriana Heguy, Sarah E.B. Taylor, Yinan Zhu, Basil Michael, Lihua Jiang, Ruiqi Jian, Anita S. Chong, Robert L. Fairchild, Suvi Linna-Kuosmanen, Minna U. Kaikkonen, Vasishta Tatapudi, Marc Lorber, David Ayares, Massimo Mangiola, Navneet Narula, Nader Moazami, Harvey Pass, Ramin S. Herati, Adam Griesemer, Manolis Kellis, Michael P. Snyder, Robert A. Montgomery, Jef D. Boeke, Brendan J. Keating

Research output: Contribution to journalArticlepeer-review


In a previous study, heart xenografts from 10-gene-edited pigs transplanted into two human decedents did not show evidence of acute-onset cellular- or antibody-mediated rejection. Here, to better understand the detailed molecular landscape following xenotransplantation, we carried out bulk and single-cell transcriptomics, lipidomics, proteomics and metabolomics on blood samples obtained from the transplanted decedents every 6 h, as well as histological and transcriptomic tissue profiling. We observed substantial early immune responses in peripheral blood mononuclear cells and xenograft tissue obtained from decedent 1 (male), associated with downstream T cell and natural killer cell activity. Longitudinal analyses indicated the presence of ischemia reperfusion injury, exacerbated by inadequate immunosuppression of T cells, consistent with previous findings of perioperative cardiac xenograft dysfunction in pig-to-nonhuman primate studies. Moreover, at 42 h after transplantation, substantial alterations in cellular metabolism and liver-damage pathways occurred, correlating with profound organ-wide physiological dysfunction. By contrast, relatively minor changes in RNA, protein, lipid and metabolism profiles were observed in decedent 2 (female) as compared to decedent 1. Overall, these multi-omics analyses delineate distinct responses to cardiac xenotransplantation in the two human decedents and reveal new insights into early molecular and immune responses after xenotransplantation. These findings may aid in the development of targeted therapeutic approaches to limit ischemia reperfusion injury-related phenotypes and improve outcomes.

Original languageEnglish (US)
Pages (from-to)1448-1460
Number of pages13
JournalNature Medicine
Issue number5
StatePublished - May 2024

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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