Macrophages are characterized by a high plasticity in response to changes in tissue microenvironment, which allows them to acquire different phenotypes and to exert essential functions in complex processes, such as tissue regeneration. Here, we report that the membrane protein Cripto plays a key role in shaping macrophage plasticity in skeletal muscle during regeneration and disease. Conditional deletion of Cripto in the myeloid lineage (CriptoMy-LOF ) perturbs MP plasticity in acutely injured muscle and in mouse models of Duchenne muscular dystrophy (mdx). Specifically, CriptoMy-LOF macrophages infiltrate the muscle, but fail to properly expand as anti-inflammatory CD206+ macrophages, which is due, at least in part, to aberrant activation of TGFβ/Smad signaling. This reduction in macrophage plasticity disturbs vascular remodeling by increasing Endothelial-to-Mesenchymal Transition (EndMT), reduces muscle regenerative potential, and leads to an exacerbation of the dystrophic phenotype. Thus, in muscle-infiltrating macrophages, Cripto is required to promote the expansion of the CD206+ anti-inflammatory macrophage type and to restrict the EndMT process, providing a direct functional link between this macrophage population and endothelial cells.

中文翻译：

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Cripto塑造巨噬细胞可塑性并限制受伤和患病骨骼肌的EndMT。

巨噬细胞的特征是对组织微环境的变化具有高度可塑性，这使它们能够获得不同的表型，并在复杂的过程（例如组织再生）中发挥重要作用。在这里，我们报道膜蛋白Cripto在再生和疾病过程中在塑造骨骼肌巨噬细胞可塑性中起关键作用。有条件地删除髓系中的Cripto（CriptoMy-LOF）会扰乱急性受伤的肌肉和Duchenne肌肉营养不良（mdx）小鼠模型中的MP可塑性。具体而言，CriptoMy-LOF巨噬细胞浸润肌肉，但不能作为抗炎CD206 +巨噬细胞正常扩张，这至少部分是由于TGFβ/ Smad信号转导异常引起的。巨噬细胞可塑性的降低通过增加内皮细胞向间质转化（EndMT）干扰了血管重塑，降低了肌肉的再生潜能，并导致营养不良性表型恶化。因此，在肌肉浸润性巨噬细胞中，需要Cripto促进CD206 +抗炎巨噬细胞类型的扩增并限制EndMT进程，从而在该巨噬细胞群和内皮细胞之间提供直接的功能联系。