Macrophages decide between regeneration and fibrosis in muscle

Muñoz‐Cánoves, Pura; Serrano, Antonio L.

doi:10.1016/j.tem.2015.07.005

Cited by 56 publications

(48 citation statements)

References 11 publications

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“…We indeed demonstrated that the lack of Nfix in two different dystrophic animal models improves both morphological and functional parameters associated to the disease, by promoting a more oxidative musculature and by slowing down muscle regeneration [28]. Different studies have shown that the improvement of dystrophies correlates with a decrease of MPs infiltration [30,32]. While MPs are necessary for muscle regeneration upon acute injury, they are deleterious in the case of chronic injury.…”

Section: Discussionmentioning

confidence: 65%

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The Transcription Factor Nfix Requires RhoA-ROCK1 Dependent Phagocytosis to Mediate Macrophage Skewing during Skeletal Muscle Regeneration

Saclier

Lapi

Bonfanti

et al. 2020

Cells

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Macrophages (MPs) are immune cells which are crucial for tissue repair. In skeletal muscle regeneration, pro-inflammatory cells first infiltrate to promote myogenic cell proliferation, then they switch into an anti-inflammatory phenotype to sustain myogenic cells differentiation and myofiber formation. This phenotypical switch is induced by dead cell phagocytosis. We previously demonstrated that the transcription factor Nfix, a member of the nuclear factor I (Nfi) family, plays a pivotal role during muscle development, regeneration and in the progression of muscular dystrophies. Here, we show that Nfix is mainly expressed by anti-inflammatory macrophages. Upon acute injury, mice deleted for Nfix in myeloid line displayed a significant defect in the process of muscle regeneration. Indeed, Nfix is involved in the macrophage phenotypical switch and macrophages lacking Nfix failed to adopt an anti-inflammatory phenotype and interact with myogenic cells. Moreover, we demonstrated that phagocytosis induced by the inhibition of the RhoA-ROCK1 pathway leads to Nfix expression and, consequently, to acquisition of the anti-inflammatory phenotype. Our study identified Nfix as a link between RhoA-ROCK1-dependent phagocytosis and the MP phenotypical switch, thus establishing a new role for Nfix in macrophage biology for the resolution of inflammation and tissue repair.

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Section: Discussionmentioning

confidence: 65%

“…While MPs are required for muscle regeneration, preventing MPs infiltration in dystrophic disease decreases muscle damage [30]. Thus, depending on a context of acute or chronic injury, MPs adopt a complete opposite function toward muscle cells and environment [31,32].…”

Section: Introductionmentioning

confidence: 99%

The Transcription Factor Nfix Requires RhoA-ROCK1 Dependent Phagocytosis to Mediate Macrophage Skewing during Skeletal Muscle Regeneration

Saclier

Lapi

Bonfanti

et al. 2020

Cells

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“…A prolonged inflammatory response disrupting tissue healing is not new and has been well documented in muscle disorders like muscular dystrophy. The repetitive cycles of degeneration-regeneration of myofibers as seen in muscular dystrophy causes the sequential invasion of M1 and M2 macrophages, respectively, resulting in fibrosis of the muscle [Madaro and Bouche, 2014;Mojumdar et al, 2014;Munoz-Canoves and Serrano, 2015]. Similarly, herein, the remodeling of the scaffold into a fibrotic scar-like tissue can in part be attributed to the heightened and protracted M1 response.…”

Section: Discussionmentioning

confidence: 93%

A Porcine Urinary Bladder Matrix Does Not Recapitulate the Spatiotemporal Macrophage Response of Muscle Regeneration after Volumetric Muscle Loss Injury

Aurora¹,

Corona²,

Walters³

2016

Cells Tissues Organs

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Volumetric muscle loss (VML) results in irrecoverable loss of muscle tissue making its repair challenging. VML repair with acellular extracellular matrix (ECM) scaffolds devoid of exogenous cells has shown improved muscle function, but limited de novo muscle fiber regeneration. On the other hand, studies using minced autologous and free autologous muscle grafts have reported appreciable muscle regeneration. This raises the fundamental question whether an acellular ECM scaffold can orchestrate the spatiotemporal cellular events necessary for appreciable muscle fiber regeneration. This study compares the macrophage and angiogenic responses including the remodeling outcomes of a commercially available porcine urinary bladder matrix, MatriStem™, and autologous muscle grafts. The early heightened and protracted M1 response of the scaffold indicates that the scaffold does not recapitulate the spatiotemporal macrophage response of the autograft tissue. Additionally, the scaffold only supports limited de novo muscle fiber formation and regressing vessel density. Furthermore, scaffold remodeling is accompanied by increased presence of transforming growth factor and α-smooth muscle actin, which is consistent with remodeling of the scaffold into a fibrotic scar-like tissue. The limited muscle formation and scaffold-mediated fibrosis noted in this study corroborates the findings of recent studies that investigated acellular ECM scaffolds (devoid of myogenic cells) for VML repair. Taken together, acellular ECM scaffolds when used for VML repair will likely remodel into a fibrotic scar-like tissue and support limited de novo muscle fiber regeneration primarily in the proximity of the injured musculature. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

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“…However, following tissue injury, large numbers of inflammatory monocytes, macrophage precursors, are recruited from the bone marrow via chemokine gradients and various adhesion molecules, with these recruited cells often exceeding the resident tissue macrophage population by many-fold (Davies et al, 2013; Galli et al, 2011). The recruited and resident macrophage populations proliferate and also undergo marked phenotypic and functional changes in response to growth factors and cytokines released in the local tissue microenvironment (Jenkins et al, 2011; Jenkins et al, 2013), with many recent studies identifying specialized and critically timed roles for different monocyte and macrophage activation states in tissue repair, regeneration, and fibrosis (Lech and Anders, 2013; Munoz-Canoves and Serrano, 2015; Murray and Wynn, 2011; Novak et al, 2014; Sica and Mantovani, 2012). …”

Section: Introductionmentioning

confidence: 99%

Macrophages in Tissue Repair, Regeneration, and Fibrosis

2016

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Inflammatory monocytes and resident tissue macrophages are key regulators of tissue repair, regeneration, and fibrosis. Following tissue injury, monocytes and macrophages undergo marked phenotypic and functional changes to play critical roles during the initiation, maintenance, and resolution phases of tissue repair. Disturbances in macrophage function can lead to aberrant repair, with uncontrolled inflammatory mediator and growth factor production, deficient generation of anti-inflammatory macrophages, or failed communication between macrophages and epithelial cells, endothelial cells, fibroblasts, and stem or tissue progenitor cells all contributing to a state of persistent injury, which may lead to the development of pathological fibrosis. In this review, we discuss the mechanisms that instruct macrophages to adopt pro-inflammatory, pro-wound healing, pro-fibrotic, anti-inflammatory, anti-fibrotic, pro-resolving, and tissue regenerating phenotypes following injury, and highlight how some of these mechanisms and macrophage activation states could be exploited therapeutically.

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Macrophages decide between regeneration and fibrosis in muscle

Cited by 56 publications

References 11 publications

The Transcription Factor Nfix Requires RhoA-ROCK1 Dependent Phagocytosis to Mediate Macrophage Skewing during Skeletal Muscle Regeneration

The Transcription Factor Nfix Requires RhoA-ROCK1 Dependent Phagocytosis to Mediate Macrophage Skewing during Skeletal Muscle Regeneration

A Porcine Urinary Bladder Matrix Does Not Recapitulate the Spatiotemporal Macrophage Response of Muscle Regeneration after Volumetric Muscle Loss Injury

Macrophages in Tissue Repair, Regeneration, and Fibrosis

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