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Circulating, cell-free methylated DNA reveals cellular sources of allograft injury after liver transplant (LTR cell-free DNA)

ABSTRACT: Molecular biomarkers to monitor changes after liver transplant are essential to reveal mechanisms of injury, guide clinical decision-making and improve patient outcomes. Current approaches have limited scope and are unable to differentiate between host and graft amongst the causes of graft injury. Here, we utilize circulating, cell-free methylated DNA released from dying cells to monitor cellular damages after liver transplant impacting the graft tissue as well as host organs. We expand existing cell-type-specific DNA methylation atlases curated from whole-genome bisulfite sequencing (WGBS) of healthy tissues to characterize liver cell-types relevant to injury progression and tissue repair. Liver cell-type-specific methylation blocks are validated through multi-omic data integration and found to be enriched in open chromatin and regulatory regions functionally important for the respective cell populations. Cell-free DNA (cfDNA) fragments were captured from patient serum by hybridization to CpG-rich DNA panels and mapped to the expanded DNA methylation atlases to inform tissue origins of cell types. We profiled 135 blood samples collected from 44 liver transplant patients at serial time points before and after transplant. We found that liver transplant initially results in multi-tissue cellular damage that subsequently recovers in patients with graft acceptance during the first post-operative week. Further, we show that sustained elevation of hepatocyte and biliary epithelial cfDNA beyond the first week is indicative of early-onset graft injury. Most notably, cfDNA composition can differentiate amongst causes of graft injury. Thus, cell-free methylated DNA can detect cellular damages and prompt early intervention.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262273 | GEO | 2025/03/02

REPOSITORIES: GEO

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Project description:Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for non-transplant indications, could regulate specific CRM genes and reduce the number of graft infiltrating cells during acute rejection. We treated mice with HLA-mismatched murine cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatina on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning and rational drug design. The eight transplant data sets used for discovery include GSE4315, GSE2596, GSE4470, GSE9377, GSE1563, GSE9493, GSE13440, GSE6095. The two additional independent cohorts of 151 transplant biopsies are GSE25902 and GSE1563. Not all samples from all studies were used. Only the samples marked as either AR or STA in each data set were used for analysis. The 101 samples in this study were used as case-control experiment between acute rejection (AR) and stable (STA) in renal transplant. The samples in this series are one of the three independent validation cohorts. The other two cohorts are described in GSE21374 and GSE36059

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Circulating, cell-free methylated DNA reveals cellular sources of allograft injury after liver transplant (LTR cell-free DNA)

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