Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis
By Rafael Kramann, Rebekka K Schneider, Derek P. DiRocco, Flavia G Machado, Susanne V. Fleig, P. Bondzie, Joel M Henderson, Benjamin L. Ebert, Benjamin D. Humphreys. Cell Stem Cell, 2014
863 citations recorded by the source corpus.
Summary 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 capacity, despite constituting a small fraction of the platelet-derived growth factor-β (PDGFRβ)+ cell population. Genetic lineage tracing analysis demonstrate that tissue-resident, but not circulating, Gli1+ cells proliferate following 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 these cells may be a relevant therapeutic target to prevent solid organ dysfunction following injury.
Subfields: Genetics, Molecular Biology, Surgery
View Paper: https://www.semanticscholar.org/paper/b07d6428d30cf14e1f4ad89ae5a724b761097df3
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Citations in the corpus
- Fibroblasts: origins, definitions, and functions in health and disease (2021, positive): “In fetal mice, the Hedgehog pathway member Gli1 labels mesenchymal lung cells except lipofibroblasts (Li et al., 2015).”
- Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration (2016, neutral): “We also discuss the therapeutic opportunities for targeting fibroblasts and myofibroblasts in order to restrict reactive fibrosis and to induce cardiac regeneration.”
- Transforming growth factor–β in tissue fibrosis (2020, positive): “Studies in both animal models of fibrosis and human patients suggested that activated myofibroblasts in fibrotic lesions may be derived, at least in part, from activated perivascular cells (Sava et al., 2017; Kramann et al., 2015; Dulauroy et al., 2012).”