Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature medicine, 2024-05, Vol.30 (5), p.1448-1460

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Multi-omics profiling of the blood and heart of two human decedents receiving pig heart xenografts, including single-cell studies, reveals early immune responses and perioperative cardiac xenograft dysfunction in one of the two decedents, which may be due to mismatched heart size and/or insufficient immunosuppression.