Region and cell-type resolved quantitative proteomic map of the human heart

Heart failure represents a major cause of morbidity and mortality worldwide. Single cell transcriptomics have revolutionized our understanding of cell composition and associated gene expression across human tissues. Through integrated analysis of single cell and single nucleus RNA sequencing data generated from 45 individuals, we define the cell composition of the healthy and failing human heart. We identify cell specific transcriptional signatures of heart failure and reveal the emergence of disease associated cell states. Intriguingly, cardiomyocytes converge towards a common disease associated cell state, while fibroblasts and myeloid cells undergo dramatic diversification. Endothelial cells and pericytes display global transcriptional shifts without changes in cell complexity. Collectively, our findings provide a comprehensive analysis of the cellular and transcriptomic landscape of human heart failure, identify cell type specific transcriptional programs and states associated with disease, and establish a valuable resource for the investigation of human heart failure.

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Angiotensin II Type 2 Receptor Is Upregulated in Human Heart With Interstitial Fibrosis, and Cardiac Fibroblasts Are the Major Cell Type for Its Expression

Circulation Research ◽

10.1161/01.res.83.10.1035 ◽

1998 ◽

Vol 83 (10) ◽

pp. 1035-1046 ◽

Cited By ~ 133

Author(s):

Yoshiaki Tsutsumi ◽

Hiroaki Matsubara ◽

Naohiko Ohkubo ◽

Yasukiyo Mori ◽

Yoshihisa Nozawa ◽

...

Keyword(s):

Angiotensin Ii ◽

Human Heart ◽

Interstitial Fibrosis ◽

Cardiac Fibroblasts ◽

Cell Type ◽

Major Cell Type

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Single-cell dissection of live human hearts in ischemic heart disease and heart failure reveals cell-type-specific driver genes and pathways

10.1101/2021.06.23.449672 ◽

2021 ◽

Author(s):

Suvi Linna-Kuosmanen ◽

Eloi Schmauch ◽

Kyriakitsa Galani ◽

Carles A. Boix ◽

Lei Hou ◽

...

Keyword(s):

Gene Expression ◽

Heart Failure ◽

Heart Disease ◽

Ischemic Heart Disease ◽

Single Cell ◽

Human Heart ◽

Cell Types ◽

Ischemic Heart ◽

Cell Type ◽

Cell Type Specific

Ischemic heart disease is the single most common cause of death worldwide with an annual death rate of over 9 million people. Genome-wide association studies have uncovered over 200 genetic loci underlying the disease, providing a deeper understanding of the causal mechanisms leading to it. However, in order to understand ischemic heart disease at the cellular and molecular level, it is necessary to identify the cell-type-specific circuits enabling dissection of driver variants, genes, and signaling pathways in normal and diseased tissues. Here, we provide the first detailed single-cell dissection of the cell types and disease-associated gene expression changes in the living human heart, using cardiac biopsies collected during open-heart surgery from control, ischemic heart disease, and ischemic and non-ischemic heart failure patients. We identify 84 cell types/states, grouped in 12 major cell types. We define markers for each cell type, providing the first extensive reference set for the live human heart. These major cell types include cardiovascular cells (cardiomyocytes, endothelial cells, fibroblasts), rarer cell types (B lymphocytes, neurons, Schwann cells), and rich populations of previously understudied layer-specific epicardial and endocardial cells. In addition, we reveal substantial differences in disease-associated gene expression at the cell subtype level, revealing arterial pericytes as having a central role in the pathogenesis of ischemic heart disease and heart failure. Our results demonstrate the importance of high-resolution cellular subtype mapping in gaining mechanistic insight into human cardiovascular disease.

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Abstract 16742: Single-Cell Transcriptional and Epigenomic Dissection of Human Heart in Health and Coronary Artery Disease Reveals Cell-type-Specific Driver Genes and Pathways

Circulation ◽

10.1161/circ.142.suppl_3.16742 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Suvi Linna Kuosmanen ◽

Eloi Schmauch ◽

Kyriakitsa Galani ◽

Carles Boix ◽

Yongjin P Park ◽

...

Keyword(s):

Coronary Artery Disease ◽

Single Cell ◽

Human Heart ◽

Target Genes ◽

Expression Patterns ◽

Cell Types ◽

Heart Cell ◽

Cell Type ◽

Cell Type Specific ◽

Artery Disease

Genome-wide association studies have uncovered over 200 genetic loci underlying coronary artery disease (CAD), providing great hope for a deeper understanding of the causal mechanisms leading to this disease. However, in order to understand CAD at the molecular level, it is necessary to uncover cell-type-specific circuits and to use these circuits to dissect driver variants, genes, pathways, and cell types, in normal and diseased tissues. Here, we provide the most detailed single-cell dissection of human heart cell types, using cardiac biopsies collected during open-heart surgery from healthy, CAD, and CAD-related heart failure donors, and profiling both transcriptional (scRNA-seq) and epigenomic (scATAC-seq) changes. Using this approach, we identify 12 major heart cell types, including typical cardiovascular cells (cardiomyocytes, endothelial cells, fibroblasts), rarer cell types (B cells, neurons, Schwann cells), and previously-unrecognized layer-specific epithelial and endothelial cell types. We define markers for each cell type, providing the first extensive reference set for the living human heart. In addition, we define differential gene expression patterns in CAD relative to control samples, revealing substantial differences in cell-type-specific expression of disease-related genes, emphasizing, for example, the importance of the vascular endothelium in the pathogenesis of CAD. Strikingly, further clustering of the cell types based on specific subtypes revealed important differences in their expression patterns of disease-associated genes. These changes enrich in known CAD genetic loci, enabling us to recognize their likely target genes from scRNA-seq expression changes, candidate driver variants based on scATAC-seq localization and differential DNA accessibility, and candidate upstream regulators based on their enriched motif occurrences in scATAC loci. Overall, our results highlight the relevance and potential of single-cell transcriptional and epigenomic analyses to gain new biological insights into cardiovascular disease, and to recognize novel therapeutic target genes, pathways, and the cell types where they act.

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Abstract MP143: Harnessing Glycomics to Understand Cardiac Biology and Disease

Circulation Research ◽

10.1161/res.127.suppl_1.mp143 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Christopher Ashwood ◽

Linda Berg Luecke ◽

Rebekah L Gundry

Keyword(s):

Human Heart ◽

Heart Function ◽

Heart Tissue ◽

Cardiac Biomarkers ◽

Tissue Homogenate ◽

Glycan Structure ◽

Cell Type ◽

Cell Type Specific ◽

Human Heart Tissue

Cell surface glycoproteins play critical roles in maintaining cardiac structure and function, and the glycan-moiety attached to a protein is critical for proper protein folding, stability, and signaling. Despite mounting evidence that glycan structures are key modulators of heart function and must be considered when developing cardiac biomarkers, we currently do not have a comprehensive view of the glycans present in the normal human heart. Here, we used an innovative mass spectrometry approach to generate the first glycan structure libraries for primary human heart tissue, cardiomyocytes (CM) enriched from human heart tissue, and human induced pluripotent stem cell derived CM (hiPSC-CM), containing >260 N- and O- glycans. Comparing the glycome of CM enriched from primary heart tissue to that of heart tissue homogenate, 21 structures significantly differed, and the high mannose class is increased in enriched CM. Moreover, >30% of the glycome significantly changed across 20-100 days of in vitro differentiation, and only 23% of the N -glycan structures were shared between hiPSC-CM and primary CM. Overall, these observations are an important complement to genomic, transcriptomic, and proteomic profiling and reveal new considerations for the use and interpretation of hiPSC-CM models for studies of human development, disease, and drug testing. These data are also expected to aid in the evaluation of the immunogenic potential of hiPSC-CM for transplantation. Finally, harnessing differences observed between immature, proliferative hiPSC-CM and adult primary CM may be exploited to drive in vitro differentiation towards a more mature phenotype. Building on these data, current efforts are underway to develop chamber- and cell-type specific views ( e.g. cardiomyocytes, fibroblasts) of the glycome in the healthy and failing human heart. Such analyses provide a key link to understand the role glycosylation plays in cell-type specific functions and cardiac disease. The structural differences observed here, either among cell types or stages of differentiation, require complex regulation of multiple enzymes in the biosynthetic pathway, and therefore would be challenging to measure with antibody arrays, RNAseq, or proteomics. Therefore, continued application of structure-based glycomics approaches, such as the method used here, will be essential for elucidating the roles that glycans and glycoproteins play during developmental and disease processes in the human heart.

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Ultrastructural Correlations between Clonal Human Tumor Colonies and in Vivo Neoplasms

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100053711 ◽

1982 ◽

Vol 40 ◽

pp. 210-211

Author(s):

M.J. Murphy ◽

R.R. Price ◽

J.C. Sloman

Keyword(s):

Cultured Cells ◽

Human Tumor ◽

Cell Type ◽

Tumor Mass ◽

Initial Cell ◽

Cloning Assay ◽

Human Tumor Cloning ◽

The Relationship

The in vitro human tumor cloning assay originally described by Salmon and Hamburger has been applied recently to the investigation of differential anti-tumor drug sensitivities over a broad range of human neoplasms. A major problem in the acceptance of this technique has been the question of the relationship between the cultured cells and the original patient tumor, i.e., whether the colonies that develop derive from the neoplasm or from some other cell type within the initial cell population. A study of the ultrastructural morphology of the cultured cells vs. patient tumor has therefore been undertaken to resolve this question. Direct correlation was assured by division of a common tumor mass at surgical resection, one biopsy being fixed for TEM studies, the second being rapidly transported to the laboratory for culture.

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Some Observations on Changes in Denervated Taste Buds of Circumvallate Papillae of Rabbits

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100063457 ◽

1969 ◽

Vol 27 ◽

pp. 308-309

Author(s):

Sunao Fujimoto ◽

Raymond G. Murray ◽

Assia Murray

Keyword(s):

Taste Buds ◽

Taste Bud ◽

Cell Type ◽

Dark Cells ◽

Type Iii ◽

Circumvallate Papillae ◽

Taste Bud Cells ◽

Light Cells

Taste bud cells in circumvallate papillae of rabbit have been classified into three groups: dark cells; light cells; and type III cells. Unilateral section of the 9th nerve distal to the petrosal ganglion was performed in 18 animals, and changes of each cell type in the denervated buds were observed from 6 hours to 10 days after the operation.Degeneration of nerves is evident at 12 hours (Fig. 1) and by 2 days, nerves are completely lacking in the buds. Invasion by leucocytes into the buds is remarkable from 6 to 12 hours but then decreases. Their extrusion through the pore is seen. Shrinkage and disturbance in arrangement of cells in the buds can be seen at 2 days. Degenerated buds consisting of a few irregular cells and remnants of degenerated cells are present at 4 days, but buds apparently normal except for the loss of nerve elements are still present at 6 days.

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Dendritic cells of the human epidermis: immuno-electron microscopic studies of la antigen reactivity

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100084090 ◽

1978 ◽

Vol 36 (2) ◽

pp. 644-645

Author(s):

G. Rowden ◽

M. G. Lewis ◽

T. M. Phillips

Keyword(s):

Dendritic Cells ◽

Langerhans Cells ◽

Cell Types ◽

Cell Type ◽

Electron Microscopic ◽

La Antigen ◽

Microscopic Studies ◽

A Cell ◽

C3 Receptors ◽

Antigen Reactivity

Langerhans cells of mammalian stratified squamous epithelial have proven to be an enigma since their discovery in 1868. These dendritic suprabasal cells have been considered as related to melanocytes either as effete cells, or as post divisional products. Although grafting experiments seemed to demonstrate the independence of the cell types, much confusion still exists. The presence in the epidermis of a cell type with morphological features seemingly shared by melanocytes and Langerhans cells has been especially troublesome. This so called "indeterminate", or " -dendritic cell" lacks both Langerhans cells granules and melanosomes, yet it is clearly not a keratinocyte. Suggestions have been made that it is related to either Langerhans cells or melanocyte. Recent studies have unequivocally demonstrated that Langerhans cells are independent cells with immune function. They display Fc and C3 receptors on their surface as well as la (immune region associated) antigens.

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