1. Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.
- Author
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Kramann R, Schneider RK, DiRocco DP, Machado F, Fleig S, Bondzie PA, Henderson JM, Ebert BL, and Humphreys BD
- Subjects
- Animals, Antigens metabolism, Aorta drug effects, Aorta pathology, Aorta physiopathology, Blood Vessels drug effects, Blood Vessels metabolism, Blood Vessels pathology, Bone Marrow Cells drug effects, Bone Marrow Cells metabolism, Cell Differentiation drug effects, Cell Lineage drug effects, Cells, Cultured, Colony-Forming Units Assay, Diphtheria Toxin pharmacology, Endothelial Cells cytology, Endothelial Cells drug effects, Endothelial Cells metabolism, Fibrosis metabolism, Heart Ventricles drug effects, Heart Ventricles pathology, Heart Ventricles physiopathology, Homeostasis drug effects, Humans, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells drug effects, Mesenchymal Stem Cells ultrastructure, Mice, Myofibroblasts cytology, Myofibroblasts metabolism, Neovascularization, Physiologic drug effects, Organ Specificity drug effects, Pericytes drug effects, Pericytes metabolism, Pericytes pathology, Proteoglycans metabolism, Receptor, Platelet-Derived Growth Factor beta metabolism, Stem Cell Niche drug effects, Zinc Finger Protein GLI1, Fibrosis pathology, Kruppel-Like Transcription Factors metabolism
- 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.)
- Published
- 2015
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