RT Journal Article
SR Electronic
T1 Single-cell dissection of live human hearts in ischemic heart disease and heart failure reveals cell-type-specific driver genes and pathways
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.23.449672
DO 10.1101/2021.06.23.449672
A1 Suvi Linna-Kuosmanen
A1 Eloi Schmauch
A1 Kyriakitsa Galani
A1 Carles A. Boix
A1 Lei Hou
A1 Tiit Örd
A1 Anu Toropainen
A1 Lindsey K. Stolze
A1 Elamaran Meibalan
A1 Julio C. Mantero
A1 Ashley Renfro
A1 Johannes Ojanen
A1 Leandro Z. Agudelo
A1 Maija Hollmen
A1 Juho Jalkanen
A1 Jarmo Gunn
A1 Pasi Tavi
A1 Casey E. Romanoski
A1 Calum A. MacRae
A1 Minna U. Kaikkonen
A1 Guillermo Garcia-Cardena
A1 Tuomas Kiviniemi
A1 Manolis Kellis
YR 2021
UL http://biorxiv.org/content/early/2021/06/24/2021.06.23.449672.abstract
AB 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 t 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.Competing Interest StatementThe authors have declared no competing interest.