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Single Cell and Spatial Transcriptomics Identify Novel Immune-Stromal Interactions in Cardiac Allograft Vasculopathy
Benjamin Kopecky1, Macee Owen2, Daniel Li1
1Division of Cardiology, Department of Medicine, Washington University School of Medicine, St. Louis, MO.
Insights
Cardiac allograft vasculopathy (CAV), a major cause of heart transplant failure, involves neointimal hyperplasia. This study identifies type 1 interferon-mediated inflammation driven by vascular smooth muscle cells and macrophages as a key driver, suggesting Ruxolitinib as a potential therapy.
Area of Science:
- Cardiovascular Biology
- Immunology
- Transplantation Science
Background:
- Cardiac allograft vasculopathy (CAV) is the primary cause of death in heart transplant recipients, characterized by neointimal hyperplasia.
- Current therapeutic options for CAV are limited, often necessitating retransplantation.
- The specific cellular and molecular mechanisms driving CAV pathogenesis remain largely undefined.
Purpose of the Study:
- To transcriptionally characterize CAV and define its neointimal microenvironment using advanced single-cell and spatial transcriptomic techniques.
- To identify unique cellular players and molecular signals involved in CAV pathogenesis.
- To explore potential therapeutic targets for preventing or reversing CAV progression.
Main Methods:
- Single-cell RNA sequencing and spatial transcriptomics of human coronary arteries from CAV patients, atherosclerotic disease patients, and controls.
- Comparative transcriptional analysis to identify a unique CAV signature.
- In vivo validation using a mouse model of CAV treated with interferon blockade (Ruxolitinib).
Main Results:
- A distinct transcriptional signature for CAV was identified, differentiating it from other coronary artery diseases.
- Modulated vascular smooth muscle cells and specific macrophage subsets were found to dominate the CAV neointima.
- These cell types appear to interact, propagating type 1 interferon (IFN)-mediated inflammation.
- Interferon blockade with Ruxolitinib significantly reduced CAV incidence and improved allograft survival in a mouse model.
Conclusions:
- This study provides a comprehensive characterization of the cellular and transcriptional landscape of CAV.
- Type 1 interferon signaling, driven by vascular smooth muscle cells and macrophages, is implicated as a key pathway in CAV pathogenesis.
- Targeting interferon signaling, for example with Ruxolitinib, represents a promising therapeutic strategy for CAV.
Abstract:
Cardiac allograft vasculopathy (CAV) is the leading cause of mortality in heart transplant recipients. Despite the prevalence of CAV, there are no targeted therapeutic options to prevent or reverse disease progression, and patients ultimately require retransplant. CAV is defined by progressive neointimal hyperplasia in donor heart coronary arteries, leading to luminal obliteration and ultimately allograft failure or sudden cardiac death. Although immune and stromal cell interactions are believed to play a key role in CAV pathogenesis, the specific cellular players and molecular signals driving disease remain undefined. In this study, we leverage single-cell RNA sequencing and spatial transcriptomics of human coronary arteries to transcriptionally characterize CAV and define the neointimal microenvironment. We compare arteries with CAV to atherosclerotic coronary artery disease and non-disease controls to identify a unique CAV transcriptional signature. Integration of single-cell RNA sequencing and spatial transcriptomic datasets revealed that modulated vascular smooth muscle cells and macrophage subsets dominate the CAV neointima and suggest that these cells interact to propagate type 1 interferon (IFN)-mediated inflammation. In a mouse CAV model, we demonstrate that interferon blockade with Ruxolitinib significantly reduced the incidence of CAV and prolonged allograft survival. Collectively, this study offers a novel and detailed characterization of the unique cellular and transcriptional landscape of CAV and identify a candidate pathway that may underly CAV pathogenesis, which could serve as a new therapeutic target for this devastating disease.
