Cellular dynamics in pig-to-human kidney xenotransplantation

Wanqing Pan, Weimin Zhang, Binghan Zheng, Brendan R. Camellato, Jeffrey Stern, Ziyan Lin, Alireza Khodadadi-Jamayran, Jacqueline Kim, Philip Sommer, Karen Khalil, Elaina Weldon, Jiangshan Bai, Yinan Zhu, Peter Meyn, Adriana Heguy, Massimo Mangiola, Adam Griesemer, Brendan J. Keating, Robert A. Montgomery, Bo XiaJef D. Boeke

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
JournalMed
DOIs
StateAccepted/In press - 2024

Keywords

  • antibody-mediated rejection
  • cell proliferation
  • genetic engineering
  • immune response
  • longitudinal RNA-seq
  • porcine kidney
  • scRNA-seq
  • tissue repair
  • Translation to patients
  • xenotransplantation

ASJC Scopus subject areas

  • General Medicine

Fingerprint

Dive into the research topics of 'Cellular dynamics in pig-to-human kidney xenotransplantation'. Together they form a unique fingerprint.

Cite this