Kramann Rafael, Schneider Rebekka K, DiRocco Derek P, Machado Flavia, Fleig Susanne, Bondzie Philip A, Henderson Joel M, Ebert Benjamin L, Humphreys Benjamin D
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.
Division of Hematology, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Cell Stem Cell. 2015 Jan 8;16(1):51-66. doi: 10.1016/j.stem.2014.11.004. Epub 2014 Nov 20.
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.
间充质干细胞（MSCs）存在于包括肾脏、肺、肝脏和心脏在内的许多器官的血管周围微环境中，尽管它们在这些组织中的作用尚不清楚。在这里，我们证明Gli1标记了对器官纤维化有显著贡献的血管周围MSC样细胞。在体外，Gli1(+)细胞表达典型的MSC标志物，具有三系分化能力，并具有集落形成活性，尽管它们仅占血小板衍生生长因子-β（PDGFRβ）(+)细胞群体的一小部分。遗传谱系追踪分析表明，组织驻留而非循环的Gli1(+)细胞在肾脏、肺、肝脏或心脏损伤后增殖，从而产生肌成纤维细胞。在诱导性心力衰竭模型中，对这些细胞进行基因消融可显著改善肾脏和心脏纤维化，并保留射血分数。这些发现表明血管周围Gli1(+) MSC样细胞是器官纤维化的主要细胞来源，并证明这些细胞可能是预防损伤后实体器官功能障碍的相关治疗靶点。
