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

Area of Science:

• Immunology
• Cardiology
• Transplantation Science

Background:

• Cardiac allograft vasculopathy (CAV) is the primary cause of death after heart transplantation, lacking effective treatments.
• CAV involves neointimal hyperplasia in donor arteries, leading to occlusion and graft failure.
• The cellular and molecular drivers of CAV remain incompletely understood.

Purpose of the Study:

• To characterize the cellular and molecular microenvironment of CAV in human coronary arteries.
• To identify distinct transcriptional signatures associated with CAV.
• To explore potential therapeutic targets for preventing or reversing CAV.

Main Methods:

• Integration of single-cell RNA sequencing and spatial transcriptomics on human coronary arteries.
• Comparative analysis of arteries from CAV patients, atherosclerotic coronary artery disease patients, and non-diseased controls.
• Validation of findings using a mouse model of CAV and blockade of type 1 interferon signaling.

Main Results:

• A unique transcriptional signature for CAV was identified.
• Modulated vascular smooth muscle cells and macrophage subsets were found to dominate the CAV neointima.
• These cell subsets interact to promote type 1 interferon (IFN)-mediated inflammation.
• IFN signaling blockade with ruxolitinib significantly reduced CAV incidence and prolonged allograft survival in a mouse model.

Conclusions:

• The study defines key cellular drivers within the CAV neointima.
• Type 1 interferon signaling is identified as a critical mediator of CAV pathogenesis.
• Targeting IFN signaling, for example, with ruxolitinib, represents a promising therapeutic strategy for CAV.