Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.
Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis.
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DOI：
10.1016/j.stem.2014.11.004
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发表时间：
2015-01-08
期刊：
影响因子：
23.9
通讯作者：
Humphreys, Benjamin D.
中科院分区：
文献类型：
--
作者：
Kramann, Rafael;Schneider, Rebekka K.;DiRocco, Derek P.;Machado, Flavia;Fleig, Susanne;Bondzie, Philip A.;Henderson, Joel M.;Ebert, Benjamin L.;Humphreys, Benjamin D.
间充质干细胞（MSC）存在于许多器官的血管周围，包括肾、肺、肝和心脏，尽管它们在这些组织中的作用知之甚少。在这里，我们证明Gli1标记血管周围的MSC样细胞，大大有助于器官纤维化。在体外，Gli1+细胞表达典型的MSC标志物，表现出三系分化能力，并具有集落形成能力，尽管构成血小板衍生生长因子-β（PDGFR β）+细胞群的一小部分。遗传谱系追踪分析表明，肾脏、肺、肝脏或心脏损伤后，组织驻留但非循环的Gli 1+细胞会增殖，产生肌成纤维细胞。这些细胞的基因消融显著改善了肾脏和心脏纤维化，并在诱导的心力衰竭模型中保持了射血分数。这些发现暗示血管周围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。
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.
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