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.

Background/Aims-Factors released during liver injury, such as platelet derived growth factor-BB (PDGF) promote accumulation of myofibroblastic hepatic stellate cells (MFB) that drive the pathogenesis of cirrhosis. The Hedgehog (Hh) pathway regulates remodeling of other injured tissues. This study evaluates the hypothesis that autocrine production of Sonic hedgehog (Shh) promotes MFB growth.