Circulating cell-free DNA methylation patterns indicate cellular sources of allograft injury after liver transplant

Megan E. McNamara, Sidharth S. Jain, Kesha Oza, Vinona Muralidaran, Amber J. Kiliti, A. Patrick McDeed, Digvijay Patil, Yuki Cui, Marcel O. Schmidt, Anna T. Riegel, Alexander Kroemer () and Anton Wellstein ()
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Megan E. McNamara: Georgetown University
Sidharth S. Jain: Georgetown University
Kesha Oza: Georgetown University Medical Center
Vinona Muralidaran: Georgetown University Medical Center
Amber J. Kiliti: Georgetown University
A. Patrick McDeed: Georgetown University
Digvijay Patil: Georgetown University Medical Center
Yuki Cui: Georgetown University Medical Center
Marcel O. Schmidt: Georgetown University
Anna T. Riegel: Georgetown University
Alexander Kroemer: Georgetown University Medical Center
Anton Wellstein: Georgetown University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Post-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation. We analyzed 130 blood samples collected from 44 patients at different time points after transplant. Sequence-based methylation of cfDNA fragments were mapped to an atlas of cell-type-specific DNA methylation patterns derived from 476 methylomes of purified cells. For liver cell types, DNA methylation patterns and multi-omic data integration show distinct enrichment in open chromatin and functionally important regulatory regions. We find that multi-tissue cellular damages post-transplant recover in patients without allograft injury during the first post-operative week. However, sustained elevation of hepatocyte and biliary epithelial cfDNA within the first month indicates early-onset allograft injury. Further, cfDNA composition differentiates amongst causes of allograft injury indicating the potential for non-invasive monitoring and intervention.

Date: 2025
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DOI: 10.1038/s41467-025-60507-9

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