Cellular dynamics in pig-to-human kidney xenotransplantation

• Published in: Med (New York, N.Y. : Online) Vol. 5; no. 8; pp. 1016 - 1029.e4
• Main Authors: Pan, Wanqing, Zhang, Weimin, Zheng, Binghan, Camellato, Brendan R., Stern, Jeffrey, Lin, Ziyan, Khodadadi-Jamayran, Alireza, Kim, Jacqueline, Sommer, Philip, Khalil, Karen, Weldon, Elaina, Bai, Jiangshan, Zhu, Yinan, Meyn, Peter, Heguy, Adriana, Mangiola, Massimo, Griesemer, Adam, Keating, Brendan J., Montgomery, Robert A., Xia, Bo, Boeke, Jef D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.08.2024
• Subjects: antibody-mediated rejection; cell proliferation; genetic engineering; immune response; longitudinal RNA-seq; porcine kidney; scRNA-seq; tissue repair; xenotransplantation; scRNA-seq; cell proliferation; immune response; xenotransplantation; longitudinal RNA-seq; porcine kidney; Translation to patients; genetic engineering; tissue repair; antibody-mediated rejection
• ISSN: 2666-6340; 2666-6340
• DOI: 10.1016/j.medj.2024.05.003

Xenotransplantation of genetically engineered porcine organs has the potential to address the challenge of organ donor shortage. Two cases of porcine-to-human kidney xenotransplantation were performed, yet the physiological effects on the xenografts and the recipients’ immune responses remain largely uncharacterized. We performed single-cell RNA sequencing (scRNA-seq) and longitudinal RNA-seq analyses of the porcine kidneys to dissect xenotransplantation-associated cellular dynamics and xenograft-recipient interactions. We additionally performed longitudinal scRNA-seq of the peripheral blood mononuclear cells (PBMCs) to detect recipient immune responses across time. Although no hyperacute rejection signals were detected, scRNA-seq analyses of the xenografts found evidence of endothelial cell and immune response activation, indicating early signs of antibody-mediated rejection. Tracing the cells’ species origin, we found human immune cell infiltration in both xenografts. Human transcripts in the longitudinal bulk RNA-seq revealed that human immune cell infiltration and the activation of interferon-gamma-induced chemokine expression occurred by 12 and 48 h post-xenotransplantation, respectively. Concordantly, longitudinal scRNA-seq of PBMCs also revealed two phases of the recipients’ immune responses at 12 and 48–53 h. Lastly, we observed global expression signatures of xenotransplantation-associated kidney tissue damage in the xenografts. Surprisingly, we detected a rapid increase of proliferative cells in both xenografts, indicating the activation of the porcine tissue repair program. Longitudinal and single-cell transcriptomic analyses of porcine kidneys and the recipient’s PBMCs revealed time-resolved cellular dynamics of xenograft-recipient interactions during xenotransplantation. These cues can be leveraged for designing gene edits and immunosuppression regimens to optimize xenotransplantation outcomes. This work was supported by NIH RM1HG009491 and DP5OD033430. [Display omitted] •Human immune cells infiltrated into porcine kidney xenografts as early as 12 h pXTx•Longitudinal scRNA-seq of human PBMCs revealed two phases of immune response•Xenografts undergo global inflammatory tissue-damage-associated gene expression•Porcine kidneys rapidly activated cell proliferation pXTx Xenotransplantation of genetically engineered porcine organs holds the potential to address the challenge of organ donor shortage. Early trials of porcine kidney xenotransplantation have been performed on brain-dead human recipients, but the cellular dynamics between xenografts and the recipients’ immune responses remain largely uncharacterized. By employing single-cell and longitudinal RNA sequencing, Pan et al. uncovered the infiltration of human immune cells into the xenografts and the activation of recipients’ immune response, suggesting an early sign of antibody-mediated rejection. Remarkably, the porcine kidney rapidly stimulated cell proliferation, indicating the activation of a tissue repair program post-transplantation. These insights will contribute to the design of new genetically engineered porcine models for optimized xenotransplantation outcomes. Longitudinal and single-cell RNA-seq analyses of two pig-to-human kidney xenotransplantation cases revealed early signs of antibody-mediated rejection and rapid activation of porcine kidney cell proliferation, indicating tissue repair. These insights can guide future strategies to optimize pig-to-human kidney xenotransplantation.