PDGFRα signalling promotes fibrogenic responses in collagen-producing cells in Duchenne muscular dystrophy.
PDGFRα signalling promotes fibrogenic responses in collagen-producing cells in Duchenne muscular dystrophy.
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DOI：
10.1002/path.4801
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发表时间：
2016-12
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通讯作者：
Reyes M
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作者：
Ieronimakis N;Hays A;Prasad A;Janebodin K;Duffield JS;Reyes M
纤维化是杜氏肌营养不良症（DMD）的一个特征，然而导致DMD纤维化的细胞和分子机制尚不清楚。利用colagen1a1 - GFP转基因鉴定暴露于毒性损伤的野生型小鼠或抗肌营养不良蛋白基因位点（mdx）突变的小鼠中产生胶原- 1基质的细胞，作为DMD模型，我们研究了骨骼肌损伤/修复和纤维化的机制。PDGFRα仅限于Sca1+、CD45−间充质祖细胞。使用可诱导的CreER/LoxP体细胞重组的命运定位实验表明，这些祖细胞在损伤或DMD中扩增成为PDGFRα+， Col1a1 - GFP+基质形成的成纤维细胞，而肌肉纤维不会成为成纤维细胞，但却是PDGFRα配体PDGF - AA的重要来源。而在肌肉PDGFRα的毒素损伤/修复中，信号在DMD模型的再生阶段短暂上调，而在人类DMD中，它长期过度激活。在损伤/修复过程中，在胶原- I+成纤维细胞中条件表达组成活性PDGFRα D842V突变，阻碍了修复阶段，反而促进了纤维化。在DMD中，用crenolanib（一种高选择性PDGFRα/β酪氨酸激酶抑制剂）治疗mdx小鼠，可减少纤维化，改善肌肉力量，并与PDGFRα信号传导的下游效应物Src活性降低相关。这些观察结果与PDGFRα激活间充质祖细胞通常调节损伤肌肉修复的模型一致，但在DMD中，该途径的持续和过度激活直接驱动纤维化并阻碍修复。PDGFRα途径是治疗进展性DMD的潜在新靶点。©2016作者。由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版的病理学杂志。
Fibrosis is a characteristic of Duchenne muscular dystrophy (DMD), yet the cellular and molecular mechanisms responsible for DMD fibrosis are poorly understood. Utilizing the Collagen1a1‐GFP transgene to identify cells producing Collagen‐I matrix in wild‐type mice exposed to toxic injury or those mutated at the dystrophin gene locus (mdx) as a model of DMD, we studied mechanisms of skeletal muscle injury/repair and fibrosis. PDGFRα is restricted to Sca1+, CD45− mesenchymal progenitors. Fate‐mapping experiments using inducible CreER/LoxP somatic recombination indicate that these progenitors expand in injury or DMD to become PDGFRα+, Col1a1‐GFP+ matrix‐forming fibroblasts, whereas muscle fibres do not become fibroblasts but are an important source of the PDGFRα ligand, PDGF‐AA. While in toxin injury/repair of muscle PDGFRα, signalling is transiently up‐regulated during the regenerative phase in the DMD model and in human DMD it is chronically overactivated. Conditional expression of the constitutively active PDGFRα D842V mutation in Collagen‐I+ fibroblasts, during injury/repair, hindered the repair phase and instead promoted fibrosis. In DMD, treatment of mdx mice with crenolanib, a highly selective PDGFRα/β tyrosine kinase inhibitor, reduced fibrosis, improved muscle strength, and was associated with decreased activity of Src, a downstream effector of PDGFRα signalling. These observations are consistent with a model in which PDGFRα activation of mesenchymal progenitors normally regulates repair of the injured muscle, but in DMD persistent and excessive activation of this pathway directly drives fibrosis and hinders repair. The PDGFRα pathway is a potential new target for treatment of progressive DMD. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.