Single-cell analysis uncovers fibroblast heterogeneity and criteria for fibroblast and mural cell identification and discrimination

Lars Muhl (), Guillem Genové, Stefanos Leptidis, Jianping Liu, Liqun He, Giuseppe Mocci, Ying Sun, Sonja Gustafsson, Byambajav Buyandelger, Indira V. Chivukula, Åsa Segerstolpe, Elisabeth Raschperger, Emil M. Hansson, Johan L. M. Björkegren, Xiao-Rong Peng, Michael Vanlandewijck, Urban Lendahl and Christer Betsholtz ()
Additional contact information
Lars Muhl: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Guillem Genové: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Stefanos Leptidis: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Jianping Liu: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Liqun He: Tianjin Medical University General Hospital, Tianjin Neurological Institute, Key Laboratory of Post-Neuroinjury, Neuro-Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City
Giuseppe Mocci: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Ying Sun: Genetics and Pathology, Rudbeck Laboratory, Uppsala University
Sonja Gustafsson: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Byambajav Buyandelger: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Indira V. Chivukula: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Åsa Segerstolpe: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Elisabeth Raschperger: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Emil M. Hansson: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Johan L. M. Björkegren: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Xiao-Rong Peng: Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM) BioPharmaceuticals R&D, AstraZeneca
Michael Vanlandewijck: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Urban Lendahl: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre
Christer Betsholtz: Karolinska Institutet/AstraZeneca Integrated Cardio Metabolic Centre

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract Many important cell types in adult vertebrates have a mesenchymal origin, including fibroblasts and vascular mural cells. Although their biological importance is undisputed, the level of mesenchymal cell heterogeneity within and between organs, while appreciated, has not been analyzed in detail. Here, we compare single-cell transcriptional profiles of fibroblasts and vascular mural cells across four murine muscular organs: heart, skeletal muscle, intestine and bladder. We reveal gene expression signatures that demarcate fibroblasts from mural cells and provide molecular signatures for cell subtype identification. We observe striking inter- and intra-organ heterogeneity amongst the fibroblasts, primarily reflecting differences in the expression of extracellular matrix components. Fibroblast subtypes localize to discrete anatomical positions offering novel predictions about physiological function(s) and regulatory signaling circuits. Our data shed new light on the diversity of poorly defined classes of cells and provide a foundation for improved understanding of their roles in physiological and pathological processes.

Date: 2020
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DOI: 10.1038/s41467-020-17740-1

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