Single-nuclear gene expression profiles of cells of human myocardial tissue obtained after heart transplantation.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE203548 | GEO | 2022/06/07
REPOSITORIES: GEO
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Project description: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.
2026-03-06 | GSE317680 | GEO
Project description: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 characterized 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.
2026-03-06 | GSE316390 | GEO
Project description:Acute rejection episodes trigger chronic renal allograft vasculopathy. Numerous leukocytes, predominantly monocytes, accumulate in graft blood vessels during reversible acute rejection preceding chronic rejection of rat kidneys. We speculate that they contribute to transplant vasculopathy and set out to characterize them. Allogeneic renal transplantation was performed in the Fischer 344 to Lewis rat strain combination, Lewis isografts served as controls. Leukocytes were harvested by intensive perfusion of graft blood vessels and subjected to flow cytometry, quantitative RT-PCR and genome-wide transcriptional profiling.
2010-09-24 | GSE18266 | GEO
Project description:Acute rejection episodes trigger chronic renal allograft vasculopathy. Numerous leukocytes, predominantly monocytes, accumulate in graft blood vessels during reversible acute rejection preceding chronic rejection of rat kidneys. We speculate that they contribute to transplant vasculopathy and set out to characterize them. Allogeneic renal transplantation was performed in the Fischer 344 to Lewis rat strain combination, Lewis isografts served as controls. Leukocytes were harvested by intensive perfusion of graft blood vessels and subjected to flow cytometry, quantitative RT-PCR and genome-wide transcriptional profiling. Kidneys of LEW and F344 rats were transplanted in LEW rats. Five biological replicates were performed for both isogenic and allogenic transplantation. Transcriptomes of allogenics were compared to isogenics on 5 dual-color hybridizations.
2010-09-24 | E-GEOD-18266 | biostudies-arrayexpress
Project description:Long-term survival of cardiac transplant recipients remains a significant hurdle largely due to cardiac allograft vasculopathy (CAV) as an expression of chronic rejection (CR). Currently, coronary angiography and intravascular ultrasound, invasive and expensive modalities, are considered the standard for diagnosis of CAV. In the current study, we combined assessment of blood mRNA and proteins to identify potential biomarkers for diagnosis of CAV. Whole blood Affymetrix microarrays and plasma iTRAQ-MALDI-TOF/TOF proteomic analyses were carried out on 25 cardiac transplant patient samples. CAV diagnosis was made based on blinded quantitative analysis of angiograms, intravascular ultrasound images and clinical chart review. The genomics and proteomics data were assessed by moderated t-tests and discriminant analysis. Two panels of 10 differentially expressed genes (FDR<5%), and 10 proteins with differential relative levels (p-values<0.025) between CAV and non-CAV samples were independently identified. Classification of new test samples revealed that the 10 genes together can discriminate between CAV and non-CAV samples with 83% sensitivity and specificity. Classification of the same samples using the 10 PGC’s dropped the sensitivity to 67%. A combinatorial panel derived from the genomic and proteomic panels provided improvement in performance, at 100% sensitivity and 83% specificity. Leave-one-out cross validation showed similar results. Genomic, proteomic and combinatorial blood-based biomarkers are promising as potential minimally-invasive, sensitive and specific modalities for the diagnosis of CAV. Classifier panels generated from current work are being evaluated in a prospective, multi-site observational trial.
2020-09-01 | GSE18656 | GEO
Project description:CD4 T and B cells are considered pivotal in driving immune responses in the context of allograft rejection. However, CD4 T and B cell transcriptional profiles according to type of allograft rejection is poorly characterized. We used scRNAseq to profile blood CD4 T and B cells in antibody-mediated rejection (ABMR), T cell mediated rejection (TCMR) and patients without rejection (STABLE).
2024-11-01 | GSE249006 | GEO
Project description:Alloreactive CD4+ T cells play a central role in allograft rejection, We used single cell RNA sequencing (scRNA-seq) to analyze the cell states of alloreactive CD4+ T cells in periphery and allografts to better understand how alloreactive CD4+ T cells drive allograft rejection.
2023-09-28 | GSE221337 | GEO
Project description:PBMCs collected from patients with or without graft dysfunction post heart transplantation were analyzed using the BD Rhapsody CITE-seq and VDJ-seq. The study groups include patients with cardiac allograft dysfunction (CAV), non-specific graft dysfunction (NGD), and normal graft function (Normal HTx).
2025-10-15 | GSE291290 | GEO
Project description:Background: Cardiac allograft vasculopathy (CAV), a diffuse thickening of the intima of the coronary arteries and microvasculature, is the leading cause of late graft failure and mortality after heart transplantation (HT). Diagnosis involves invasive coronary angiography, which carries substantial risk, and minimally-invasive approaches to CAV diagnosis are urgently needed. Using single-cell RNA-sequencing in peripheral blood mononuclear cells (PBMCs), we sought to identify cell-specific gene expression profiles in CAV. Methods: Whole blood was collected from 22 HT recipients with angiographically-confirmed CAV and 18 HT recipients without CAV. PBMCs were isolated and subjected to single-cell RNA-sequencing using a 10X Genomics microfluidic platform. Downstream analyses focused on differential expression of genes, cell compositional changes, and T cell receptor repertoire analyses. Results: Across 40 PBMC samples, we isolated 134,984 cells spanning 8 major clusters and 31 subclusters of cell types. Compositional analyses showed subtle, but significant increases in CD4+ T central memory cells, and CD14+ and CD16+ monocytes in high-grade CAV (CAV-2 and CAV-3) as compared to low-grade or absent CAV. After adjusting for age, gender, and prednisone use, 745 genes were differentially expressed in a cell-specific manner in high-grade CAV. Weighted gene co-expression network analyses showed enrichment for putative pathways involved in inflammation and angiogenesis. There were no significant differences in T cell clonality or diversity with increasing CAV severity. Conclusions: Unbiased whole transcriptomic analyses at single-cell resolution identify unique, cell-specific gene expression patterns in CAV, suggesting the potential utility of peripheral gene expression biomarkers in diagnosing CAV.
2024-12-21 | GSE271408 | GEO
Project description:Chronic rejection after organ transplantation manifests as immunosuppressant-resistant graft vascular remodeling and fibrosis, which remains the dominant driver of mortality after the first year of heart transplantation. Single-cell RNAseq analysis of MHCII-mismatched heart transplants developing chronic rejection identified graft IL-33 as a stimulator of tissue repair pathways in infiltrating myeloid cells and regulatory T cells (Tregs). Using IL-33-deficient donor mice, it was revealed that graft fibroblast-derived IL-33 potently induced Amphiregulin (Areg) expression by recipient Treg. Areg is an epidermal growth factor secreted by multiple immune cells to shape immunomodulation and tissue repair. In particular, Areg is proposed to play a major role in Treg-mediated muscle, epithelium, and nerve repair. Assessing recipient mice with Treg-specific deletion of Areg demonstrated that this pathway surprisingly contributes to chronic rejection. Specifically, heart transplants from recipients with Areg-deficient Tregs exhibited less vasculopathy and vessel-associated fibrotic niches infiltrated by recipient T cells. Mechanistically, we show that Areg does not impact Treg suppressive function, but that IL-33 mediated Treg-secretion of Areg increases fibroblast proliferation and migration. In total, these studies identify how a dysregulated repair response involving interactions between IL-33+ fibroblasts in the allograft and recipient Treg contributes to the progression of chronic rejection.
2024-12-02 | GSE235871 | GEO