Cripto shapes macrophage plasticity and restricts EndMT in injured and diseased skeletal muscle. (27th February 2020)

• Record Type: Journal Article
• Authors: Iavarone, Francescopaolo; Guardiola, Ombretta; Scagliola, Alessandra; Andolfi, Gennaro; Esposito, Federica; Serrano, Antonio; Perdiguero, Eusebio; Brunelli, Silvia; Muñoz‐Cánoves, Pura; Minchiotti, Gabriella
• Is Part Of: EMBO reports. Volume 21:Number 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-27
• Subjects: Cripto -- Duchenne muscular dystrophy -- Endothelial‐to‐Mesenchymal Transition -- macrophage plasticity -- skeletal muscle regeneration; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201949075
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: 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 (Cripto My‐LOF ) perturbs MP plasticity in acutely injured muscle and in mouse models of Duchenne muscular dystrophy (mdx). Specifically, Cripto My‐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. Synopsis: The membrane protein Cripto is an extrinsic determinant of macrophage plasticity in skeletal muscle regeneration and disease. Cripto‐dependent modulation of macrophage phenotypes controls endothelial plasticity and contributes to proper muscle repair. Cripto is predominantly expressed in expanding anti‐inflammatory macrophages in the regenerating tissue. Cripto promotes the proper accumulation of CD206 + anti‐inflammatory MPs, by modulating TGF‐β/Smad signaling. Lack of Cripto in the myeloid lineage affects vascular remodeling by increasing EndMT and collagen deposition. Abstract : The membrane protein Cripto is an extrinsic determinant of macrophage plasticity in skeletal muscle regeneration and disease. Cripto‐dependent modulation of macrophage phenotypes controls endothelial plasticity and contributes to proper muscle repair.