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<p>Cardiac allograft vasculopathy (CAV) is the leading cause of mortality after heart transplantation, yet no targeted therapies exist to prevent or reverse disease progression, and patients with CAV ultimately require a retransplant. CAV is characterized by progressive neointimal hyperplasia in donor coronary arteries, resulting in luminal occlusion and eventual allograft failure. Although immune and stromal cell interactions are thought to drive disease, the key cellular and molecular mechanisms remain poorly defined. Here we integrate single-cell RNA sequencing and spatial transcriptomics of human coronary arteries to characterize the CAV neointimal microenvironment. By comparing arteries with CAV with atherosclerotic coronary artery disease and non-diseased controls, we identify a distinct transcriptional signature of CAV. Our analysis reveals that modulated vascular smooth muscle cells and macrophage subsets dominate the neointima and interact to promote type 1 interferon (IFN)-mediated inflammation. Using a mouse model of CAV, we show that IFN signaling blockade with ruxolitinib significantly reduces CAV incidence and prolongs allograft survival. These findings define key cellular drivers of CAV and highlight IFN signaling as a potential therapeutic target.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月18日

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  • Macee C. Owen,
  • Daniel Yuhang Li,
  • Haewon Shin,
  • Wenduo Gu,
  • Alekhya Parvathaneni,
  • Farid F. Kadyrov,
  • Xiaoran Wang,
  • Maura Sticco-Ivins,
  • Gianni Bonnici,
  • Samantha L. Nelson,
  • Hao Dun,
  • Sariah Hyacinth,
  • Samantha C. Giangrasso,
  • Caroline Chou,
  • Chieh-Yu Lin,
  • Michael T. Cain,
  • Albert Pedroza,
  • Alex Dalal,
  • Karim Sallam,
  • Jack Boyd,
  • Joseph Woo,
  • Junedh M. Amrute,
  • Paul Cheng,
  • Kory J. Lavine,
  • Benjamin J. Kopecky

摘要

Cardiac allograft vasculopathy (CAV) is the leading cause of mortality after heart transplantation, yet no targeted therapies exist to prevent or reverse disease progression, and patients with CAV ultimately require a retransplant. CAV is characterized by progressive neointimal hyperplasia in donor coronary arteries, resulting in luminal occlusion and eventual allograft failure. Although immune and stromal cell interactions are thought to drive disease, the key cellular and molecular mechanisms remain poorly defined. Here we integrate single-cell RNA sequencing and spatial transcriptomics of human coronary arteries to characterize the CAV neointimal microenvironment. By comparing arteries with CAV with atherosclerotic coronary artery disease and non-diseased controls, we identify a distinct transcriptional signature of CAV. Our analysis reveals that modulated vascular smooth muscle cells and macrophage subsets dominate the neointima and interact to promote type 1 interferon (IFN)-mediated inflammation. Using a mouse model of CAV, we show that IFN signaling blockade with ruxolitinib significantly reduces CAV incidence and prolongs allograft survival. These findings define key cellular drivers of CAV and highlight IFN signaling as a potential therapeutic target.