Peter J Kennel1, Amit Saha2, Dawn A Maldonado2, Raymond Givens2, Danielle L Brunjes2, Estibaliz Castillero3, Xiaokan Zhang2, Ruiping Ji2, Alexandre Yahi4, Isaac George3, Donna M Mancini5, Antonius Koller6, Barry Fine2, Emmanuel Zorn7, Paolo C Colombo2, Nicholas Tatonetti4, Emily I Chen8, P Christian Schulze9. 1. Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York, USA; Department of Medicine, Weill-Cornell Medical College, New York, New York, USA; Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, Friedrich Schiller University Jena, Jena, Germany. 2. Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York, USA. 3. Division of Cardiothoracic Surgery, Department of Surgery, Columbia University Medical Center, New York, New York, USA. 4. Department of Biomedical Informatics, Columbia University, New York, New York, USA. 5. Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York, USA; Mount Sinai Heart, New York, New York, USA. 6. The Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, USA. 7. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USA. 8. Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York, USA; Department of Pharmacology, Columbia University Medical Center, New York, New York, USA. 9. Division of Cardiology, Department of Medicine, Columbia University Medical Center, New York, New York, USA; Department of Internal Medicine I, Division of Cardiology, University Hospital Jena, Friedrich Schiller University Jena, Jena, Germany. Electronic address: christian.schulze@med.uni-jena.de.
Abstract
BACKGROUND: Exosomes are cell-derived circulating vesicles that play an important role in cell-cell communication. Exosomes are actively assembled and carry messenger RNAs, microRNAs and proteins. The "gold standard" for cardiac allograft surveillance is endomyocardial biopsy (EMB), an invasive technique with a distinct complication profile. The development of novel, non-invasive methods for the early diagnosis of allograft rejection is warranted. We hypothesized that the exosomal proteome is altered in acute rejection, allowing for a distinction between non-rejection and rejection episodes. METHODS: Serum samples were collected from heart transplant (HTx) recipients with no rejection, acute cellular rejection (ACR) and antibody-mediated rejection (AMR). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of serum exosome was performed using a mass spectrometer (Orbitrap Fusion Tribrid). RESULTS: Principal component analysis (PCA) revealed a clustering of 3 groups: (1) control and heart failure (HF); (2) HTx without rejection; and (3) ACR and AMR. A total of 45 proteins were identified that could distinguish between groups (q < 0.05). Comparison of serum exosomal proteins from control, HF and non-rejection HTx revealed 17 differentially expressed proteins in at least 1 group (q < 0.05). Finally, comparisons of non-rejection HTx, ACR and AMR serum exosomes revealed 15 differentially expressed proteins in at least 1 group (q < 0.05). Of these 15 proteins, 8 proteins are known to play a role in the immune response. Of note, the majority of proteins identified were associated with complement activation, adaptive immunity such as immunoglobulin components and coagulation. CONCLUSIONS: Characterizing of circulating exosomal proteome in different cardiac disease states reveals unique protein expression patterns indicative of the respective pathologies. Our data suggest that HTx and allograft rejection alter the circulating exosomal protein content. Exosomal protein analysis could be a novel approach to detect and monitor acute transplant rejection and lead to the development of predictive and prognostic biomarkers.
BACKGROUND: Exosomes are cell-derived circulating vesicles that play an important role in cell-cell communication. Exosomes are actively assembled and carry messenger RNAs, microRNAs and proteins. The "gold standard" for cardiac allograft surveillance is endomyocardial biopsy (EMB), an invasive technique with a distinct complication profile. The development of novel, non-invasive methods for the early diagnosis of allograft rejection is warranted. We hypothesized that the exosomal proteome is altered in acute rejection, allowing for a distinction between non-rejection and rejection episodes. METHODS: Serum samples were collected from heart transplant (HTx) recipients with no rejection, acute cellular rejection (ACR) and antibody-mediated rejection (AMR). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of serum exosome was performed using a mass spectrometer (Orbitrap Fusion Tribrid). RESULTS: Principal component analysis (PCA) revealed a clustering of 3 groups: (1) control and heart failure (HF); (2) HTx without rejection; and (3) ACR and AMR. A total of 45 proteins were identified that could distinguish between groups (q < 0.05). Comparison of serum exosomal proteins from control, HF and non-rejection HTx revealed 17 differentially expressed proteins in at least 1 group (q < 0.05). Finally, comparisons of non-rejection HTx, ACR and AMR serum exosomes revealed 15 differentially expressed proteins in at least 1 group (q < 0.05). Of these 15 proteins, 8 proteins are known to play a role in the immune response. Of note, the majority of proteins identified were associated with complement activation, adaptive immunity such as immunoglobulin components and coagulation. CONCLUSIONS: Characterizing of circulating exosomal proteome in different cardiac disease states reveals unique protein expression patterns indicative of the respective pathologies. Our data suggest that HTx and allograft rejection alter the circulating exosomal protein content. Exosomal protein analysis could be a novel approach to detect and monitor acute transplant rejection and lead to the development of predictive and prognostic biomarkers.
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