Abstract
Mesenchymal stem cells (MSCs) reside in the perivascular niche of many organs, including kidney, lung, liver, and heart, although their roles in these tissues are poorly understood. Here, we demonstrate that Gli1 marks perivascular MSC-like cells that substantially contribute to organ fibrosis. In vitro, Gli1(+) cells express typical MSC markers, exhibit trilineage differentiation capacity, and possess colony-forming activity, despite constituting a small fraction of the platelet-derived growth factor-β (PDGFRβ)(+) cell population. Genetic lineage tracing analysis demonstrates that tissue-resident, but not circulating, Gli1(+) cells proliferate after kidney, lung, liver, or heart injury to generate myofibroblasts. Genetic ablation of these cells substantially ameliorates kidney and heart fibrosis and preserves ejection fraction in a model of induced heart failure. These findings implicate perivascular Gli1(+) MSC-like cells as a major cellular origin of organ fibrosis and demonstrate that these cells may be a relevant therapeutic target to prevent solid organ dysfunction after injury.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens / metabolism
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Aorta / drug effects
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Aorta / pathology
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Aorta / physiopathology
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Blood Vessels / drug effects
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Blood Vessels / metabolism
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Blood Vessels / pathology
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / metabolism
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Cell Differentiation / drug effects
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Cell Lineage / drug effects
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Cells, Cultured
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Colony-Forming Units Assay
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Diphtheria Toxin / pharmacology
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Fibrosis / metabolism
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Fibrosis / pathology*
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Heart Ventricles / drug effects
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Heart Ventricles / pathology
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Heart Ventricles / physiopathology
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Homeostasis / drug effects
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Humans
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Kruppel-Like Transcription Factors / metabolism*
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Mesenchymal Stem Cells / cytology
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / ultrastructure
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Mice
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Myofibroblasts / cytology
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Myofibroblasts / metabolism
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Neovascularization, Physiologic / drug effects
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Organ Specificity / drug effects
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Pericytes / drug effects
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Pericytes / metabolism
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Pericytes / pathology
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Proteoglycans / metabolism
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Receptor, Platelet-Derived Growth Factor beta / metabolism
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Stem Cell Niche / drug effects
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Zinc Finger Protein GLI1
Substances
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Antigens
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Diphtheria Toxin
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Gli1 protein, mouse
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Kruppel-Like Transcription Factors
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Proteoglycans
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Zinc Finger Protein GLI1
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chondroitin sulfate proteoglycan 4
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Receptor, Platelet-Derived Growth Factor beta