title: Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.
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.
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Nephrology and Clinical Immunology and Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. Electronic address: rkramann@gmx.net.
authors.forename: Rafael
authors.initials: R
authors.lastname: Kramann
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Derek P
authors.initials: DP
authors.lastname: DiRocco
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Flavia
authors.initials: F
authors.lastname: Machado
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fleig
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Bondzie
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Henderson
authors.affiliation: Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
authors.affiliation: Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: bhumphreys@partners.org.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Humphreys
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004167:Diphtheria Toxin / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000648:ultrastructure; D051379:Mice; D058628:Myofibroblasts / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D055153:Stem Cell Niche / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D004167:Diphtheria Toxin; D051741:Kruppel-Like Transcription Factors; D011509:Proteoglycans; D020797:Receptor, Platelet-Derived Growth Factor beta; D000071676:Zinc Finger Protein GLI1; D000099216:Chondroitin Sulfate Proteoglycan 4; C498520:Gli1 protein, mouse