Single-cell and spatial transcriptomics identify immune-stromal interactions in cardiac allograft vasculopathy.

Summary

Single-cell and spatial profiling of human coronary arteries reveals that modulated vascular smooth muscle cells and macrophages orchestrate a type I interferon–dominant inflammatory milieu in CAV. Pharmacologic IFN–JAK blockade with ruxolitinib reduced disease incidence and extended graft survival in a CAV mouse model, nominating IFN signaling as a therapeutic target.

Key Findings

• CAV neointima is dominated by modulated vascular smooth muscle cells and macrophage subsets with a distinct transcriptional signature versus atherosclerosis and controls.
• Type I interferon–mediated inflammation emerges as a central pathway via immune–stromal interactions.
• IFN–JAK blockade with ruxolitinib significantly reduced CAV incidence and prolonged allograft survival in a mouse model.

Clinical Implications

Type I IFN–JAK signaling may be a viable therapeutic axis in CAV; ruxolitinib or similar agents warrant clinical evaluation. The cellular signatures could inform biomarker development and patient stratification.

Limitations

• Human tissue heterogeneity and limited sample sizes may affect generalizability
• Mouse model may not fully recapitulate human CAV complexity or long-term safety of JAK inhibition

Future Directions

Prospective clinical trials of JAK/IFN pathway inhibition in CAV with biomarker-guided enrollment; longitudinal spatial profiling to track lesion evolution and treatment response.