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Cell Stem Cell. 2015 Jan 8;16(1):51-66. doi: 10.1016/j.stem.2014.11.004. Epub 2014 Nov 20.

Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.

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  • 1Renal 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.
  • 2Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 3Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • 4Department of Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
  • 5Division 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.
  • 6Renal 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.

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.

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PMID:
25465115
PMCID:
PMC4289444
DOI:
10.1016/j.stem.2014.11.004
[PubMed - indexed for MEDLINE]
Free PMC Article

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