Abstract
Single-cell transcriptome analysis is a powerful strategy uncovering heterogeneities of cells and their responses and molecular mechanism in developmental, physiological, and pathological processes. We have applied this technology to cardiac tissue, single-cardiomyocyte RNA- seq analysis of heart failure model mice and human failing heart, and we have uncovered heterogeneous stress response during cardiomyocyte remodeling, showing distinct transcriptional dynamics of the cardiomyocyte gene programs. However, it is difficult to simultaneously analyze transcriptomes of cardiomyocytes and non-cardiomyocytes in the archival heart tissue because of its highly interconnected feature and significant differences in cellular characteristics. We established single-nucleus RNA- seq analysis pipeline to overcome such problems and comprehensively analyze cells consist of heart tissue, to elucidate molecular mechanism in the pathogenesis of heart failure, combining the data with clinical phenotype of the disease.Single-nucleus analysis of the frozen mouse heart successfully reclassified cardiac cells by their transcriptomic features. By comparing single-nucleus RNA- seq profiles with single-cell RNA- seq profiles, we found a significant difference of mRNA localization between the cytosol and nucleus. mRNA of nuclear mitochondrial genes is preferentially localized in the cytosol, whereas that of extracellular matrix genes is in the nucleus. We also conducted single-nucleus RNA- seq analysis of the heart from patients with heart failure, again successfully reclassified cell types, and found disease specific transcriptomic landscape in heart failure. We are going to integrate single-nucleus gene expression profiles with the phenotypic characteristics such as treatment response and clinical prognosis, to reveal the molecular characteristics useful for cardiovascular precision medicine.
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