Cellular dynamics in pig-to-human kidney xenotransplantation.

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2024-08-09 Epub Date: 2024-05-21 DOI:10.1016/j.medj.2024.05.003

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 Xia, Jef D Boeke

{"title":"Cellular dynamics in pig-to-human kidney xenotransplantation.","authors":"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 Xia, Jef D Boeke","doi":"10.1016/j.medj.2024.05.003","DOIUrl":null,"url":null,"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.","PeriodicalId":29964,"journal":{"name":"Med","volume":null,"pages":null},"PeriodicalIF":12.8000,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11317223/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2024.05.003","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/5/21 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

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.

查看原文本刊更多论文

猪-人肾脏异种移植中的细胞动态。

背景：基因工程猪器官的异种移植有可能解决器官供体短缺的难题。目前已进行了两例猪-人肾脏异种移植，但异种移植物的生理效应和受者的免疫反应在很大程度上仍未定性：我们对猪肾进行了单细胞RNA测序（scRNA-seq）和纵向RNA-seq分析，以剖析异种移植相关的细胞动力学和异种移植物与受体之间的相互作用。此外，我们还对外周血单核细胞（PBMCs）进行了纵向scRNA-seq分析，以检测受体的跨时间免疫反应：尽管没有检测到超急性排斥反应信号，但对异种移植物的 scRNA-seq 分析发现了内皮细胞和免疫反应激活的证据，这表明抗体介导的排斥反应出现了早期迹象。追溯细胞的物种来源，我们在两个异种移植物中都发现了人类免疫细胞的浸润。纵向批量 RNA-seq 中的人类转录本显示，人类免疫细胞浸润和干扰素-γ 诱导的趋化因子表达激活分别发生在异种移植后 12 小时和 48 小时。与此相一致，PBMCs 的纵向 scRNA-seq 也揭示了受体在 12 小时和 48-53 小时内的两个免疫反应阶段。最后，我们观察到异种移植相关肾组织损伤在异种移植物中的全局表达特征。令人惊讶的是，我们在两个异种移植物中都检测到了增殖细胞的快速增加，这表明猪组织修复程序被激活了：结论：对猪肾脏和受体血浆细胞的纵向和单细胞转录组分析揭示了异种移植过程中异种移植物与受体相互作用的时间分辨细胞动态。这些线索可用于设计基因编辑和免疫抑制方案，以优化异种移植结果：这项工作得到了美国国立卫生研究院RM1HG009491和DP5OD033430的支持。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.