Dataset Information

Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms.

ABSTRACT: Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey's blood parameters were analyzed on days -7, -3, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.

SUBMITTER: Park MY

PROVIDER: S-EPMC7828557 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms.

Park Min Young MY Krishna Vasamsetti Bala Murali BM Kim Wan Seop WS Kang Hee Jung HJ Kim Do-Young DY Lim Byeonghwi B Cho Kahee K Kim Jun Seok JS Chee Hyun Keun HK Park Jung Hwan JH Yang Hyun Suk HS Rallabandi Harikrishna Reddy HR Ock Sun A SA Park Mi-Ryung MR Lee Heasun H Hwang In-Sul IS Kim Jun-Mo JM Oh Keon Bong KB Yun Ik Jin IJ

International journal of molecular sciences 20210113 2

Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old <i>alpha-1,3-galactosyltransferase knockout</i> (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey's blood parameters were a ...[more]

PMID: 33451076

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Project description:Heart transplantation is the gold standard for treating patients with advanced heart failure. Although improvements in immunosuppressive therapies have significantly reduced the frequency of cardiac graft rejection, the incidences of T cell-mediated rejection (TCMR) and antibody-mediated rejection remain almost unchanged. A four-archetype analysis (4AA) model, developed by Philip F. Halloran, illustrated this problem well. It provided a new dimension to improve the accuracy of diagnoses and an independent system for recalibrating the histology guidelines. However, this model was based on the invasive method of endocardial biopsy, which undoubtedly increased the postoperative risk of heart transplant patients. Currently, little is known regarding the associated genes and specific functions of the different phenotypes. We performed bioinformatics analysis (using machine-learning methods and the WGCNA algorithm) to screen for hub-specific genes related to different phenotypes, based Gene Expression Omnibus accession number GSE124897. More immune cell infiltration was observed with the ABMR, TCMR, and injury phenotypes than with the stable phenotype. Hub-specific genes for each of the four archetypes were verified successfully using an external test set (accession number GSE2596). Logistic-regression models based on TCMR-specific hub genes and common hub genes were constructed with accurate diagnostic utility (area under the curve > 0.95). RELA, NFKB1, and SOX14 were identified as transcription factors important for TCMR/injury phenotypes and common genes, respectively. Additionally, 11 Food and Drug Administration-approved drugs were chosen from the DrugBank Database for each four-archetype model. Tyrosine kinase inhibitors may be a promising new option for transplant rejection treatment. KRAS signaling in cardiac transplant rejection is worth further investigation. Our results showed that heart transplant rejection subtypes can be accurately diagnosed by detecting expression of the corresponding specific genes, thereby enabling precise treatment or medication.

Dataset Information

Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms.

Publications

Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms.

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