TY - JOUR
T1 - Cellular dynamics in pig-to-human kidney xenotransplantation
AU - Pan, Wanqing
AU - Zhang, Weimin
AU - Zheng, Binghan
AU - Camellato, Brendan R.
AU - Stern, Jeffrey
AU - Lin, Ziyan
AU - Khodadadi-Jamayran, Alireza
AU - Kim, Jacqueline
AU - Sommer, Philip
AU - Khalil, Karen
AU - Weldon, Elaina
AU - Bai, Jiangshan
AU - Zhu, Yinan
AU - Meyn, Peter
AU - Heguy, Adriana
AU - Mangiola, Massimo
AU - Griesemer, Adam
AU - Keating, Brendan J.
AU - Montgomery, Robert A.
AU - Xia, Bo
AU - Boeke, Jef D.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/8/9
Y1 - 2024/8/9
N2 - Background: 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. Methods: 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. Findings: 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. Conclusions: 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. Funding: This work was supported by NIH RM1HG009491 and DP5OD033430.
AB - Background: 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. Methods: 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. Findings: 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. Conclusions: 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. Funding: This work was supported by NIH RM1HG009491 and DP5OD033430.
KW - Translation to patients
KW - antibody-mediated rejection
KW - cell proliferation
KW - genetic engineering
KW - immune response
KW - longitudinal RNA-seq
KW - porcine kidney
KW - scRNA-seq
KW - tissue repair
KW - xenotransplantation
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U2 - 10.1016/j.medj.2024.05.003
DO - 10.1016/j.medj.2024.05.003
M3 - Article
C2 - 38776915
AN - SCOPUS:85195262404
SN - 2666-6359
VL - 5
SP - 1016-1029.e4
JO - Med
JF - Med
IS - 8
ER -