SPATIAL transcriptomics uncovered extensive molecular heterogeneity in cardiac allograft rejection, according to evidence from a longitudinal analysis of cardiac biopsies.
The study examined biopsies collected during and after histologically diagnosed rejection and analysed more than 10 million transcripts across 162,638 cells representing 28 cell types.
Researchers identified significant differences in the abundance of immune and cardiac tissue cells across acute cellular rejection, antibody mediated rejection, and mixed rejection.
Acute cellular rejection was characterised by higher proportions of CD8-positive T-cells, proliferating T-cells, B-cells, dendritic cells, fibroblasts, and macrophages.
In contrast, antibody-mediated rejection showed greater proportions of endothelial cells, plasma cells, cardiomyocytes, macrophages, and proliferating pericytes.
Distinct spatial patterns were also observed, with immune cells clustering differently according to rejection subtype.
Importantly, transcriptional analyses demonstrated substantial overlap between rejection grades and considerable variation within the same histological grade.
Principal component analysis and clustering approaches showed that molecular profiles did not separate clearly according to conventional rejection classifications, suggesting that histology alone may miss clinically relevant biological differences.
Researchers next examined patients who responded to augmented immunomodulatory treatment and those who did not.
Among 32 individuals with acute cellular rejection, 15 experienced resolution following treatment, while 17 continued to exhibit rejection.
Non-responders displayed distinct baseline molecular signatures before therapy. These biopsies showed increased expression of genes associated with T-cell activation, immune signalling, tissue injury, and remodelling.
Elevated expression of multiple T-cell receptor signalling markers and extracellular matrix remodelling genes suggested a more aggressive inflammatory state before treatment began.
Researchers also found that gene expression patterns differed markedly between acute cellular rejection and antibody mediated rejection, with acute cellular rejection demonstrating stronger activation of T-cell and interferon related pathways.
The study further identified cell-specific genes associated with cardiac allograft vasculopathy, a major form of chronic rejection.
Across all biopsy samples, researchers identified 323 significant gene and cell type associations involving 198 unique genes across 26 cell types.
Many of the genes linked to cardiac allograft vasculopathy were associated with vascular inflammation, angiogenesis, proliferation, and coagulation pathways.
Notably, molecular signals associated with future cardiac allograft vasculopathy persisted even after treatment and apparent histological resolution of rejection, indicating that residual inflammatory activity may continue despite standard therapy.
The researchers concluded that spatial transcriptomics can reveal clinically meaningful molecular heterogeneity in cardiac allograft rejection and may support future precision approaches for diagnosis, treatment selection, and long-term risk assessment following heart transplantation.
Reference
Amancherla K et al. Dynamic cellular programs of human cardiac allograft rejection revealed by spatial transcriptomics. Nat Cardiovasc Res. 2026;DOI:10.1038/s44161-026-00849-9
Featured image: Akarawut on Adobe Stock
Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.
