Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration

Fiore, Daniela; Judson, Robert N.; Low, Marcela; Lee, Sunny; Zhang, Erica; Hopkins, Claudia I.; Xu, Peter; Lenzi, Andrea; Rossi, Fábio; Lemos, Darío R.

doi:10.1016/j.scr.2016.06.007

Cited by 120 publications

(131 citation statements)

References 29 publications

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“…FAP cells are then eliminated by apoptosis that is driven by TNF released from M1-biased macrophages 31 . However, during their few days of pro-fibrotic activity, they modulate the developmental programme of MPCs to influence the course of muscle regeneration 31,88 .…”

Section: Immune Cell Interactions With Fap Cells In Musclementioning

confidence: 99%

Regulation of muscle growth and regeneration by the immune system

2017

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Diseases of muscle that are caused by pathological interactions between muscle and the immune system are devastating, but rare. However, muscle injuries that involve trauma and regeneration are fairly common, and inflammation is a clear feature of the regenerative process. Investigations of the inflammatory response to muscle injury have now revealed that the apparently nonspecific inflammatory response to trauma is actually a complex and coordinated interaction between muscle and the immune system that determines the success or failure of tissue regeneration.

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Section: Immune Cell Interactions With Fap Cells In Musclementioning

confidence: 99%

Regulation of muscle growth and regeneration by the immune system

2017

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“…Following acute injury, FAPs activate and amplify, some are eliminated by apoptosis induced by pro-inflammatory cytokines such as IL4 (Joe et al, 2010). Coculture experiments demonstrated that FAPs represent a transient source of pro-differentiation factors for driving proliferating myoblast differentiation and fusion; and it has been shown that pharmacological inhibition of FAP proliferation and differentiation, or diphtheria toxin ablation of these cells results in impaired muscle regeneration (Fiore et al, 2016;Murphy et al, 2011). On the other hand, during chronic degeneration/regeneration, FAPs are the main source of fibrosis, and in dystrophic mice, the combination of a pro-and anti-inflammatory secretome (Villalta et al, 2009) maintains FAPs survival and differentiation into matrix-producing cells similar to fibroblasts (Lemos et al, 2015).…”

Section: Cellular Regulators Of Muscle Repair and Their Regenerativementioning

confidence: 99%

Regulation and phylogeny of skeletal muscle regeneration

Baghdadi

Tajbakhsh

2018

Developmental Biology

158

135

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One of the most fascinating questions in regenerative biology is why some animals can regenerate injured structures while others cannot. Skeletal muscle has a remarkable capacity to regenerate even after repeated traumas, yet limited information is available on muscle repair mechanisms and how they have evolved. For decades, the main focus in the study of muscle regeneration was on muscle stem cells, however, their interaction with their progeny and stromal cells is only starting to emerge, and this is crucial for successful repair and reestablishment of homeostasis after injury. In addition, numerous murine injury models are used to investigate the regeneration process, and some can lead to discrepancies in observed phenotypes. This review addresses these issues and provides an overview of the some of the main regulatory cellular and molecular players involved in skeletal muscle repair.Key words: skeletal muscle, regeneration, stem cells, evolution, quiescence, injury IntroductionThe ability to regenerate tissues and structures is a prevalent feature of metazoans although there is significant variability among species ranging from limited regeneration of a tissue (birds and mammals) to regeneration involving the entire organism (cnidarians, planarians, hydra). The intriguing evolutionary loss of regenerative capacity in more complex organisms highlights the importance of identifying the underlying mechanisms responsible for these diverse regenerative strategies. One of the most studied tissues that contributes to new appendage formation is skeletal muscle, thereby making it a major focus of regeneration studies during evolution. The emergence of new lineage-tracing tools in different animal models has permitted the identification of specific progenitor cell populations and their contribution to tissue repair.Skeletal muscles allow voluntary movement and they play a key role in regulating metabolism and homeostasis in the organism. In mice and humans this tissue represents about 30-40% of the total body mass. This tissue provides an excellent tractable model to study regenerative myogenesis and the relative roles of stem and stromal cells following a single, or repeated rounds of injury. Although muscle regeneration relies mainly on its resident muscle stem (satellite) cells (MuSCs) to effect muscle repair, interactions with neighbouring stromal cells, by direct contact or via the release of soluble factors, is essential to restore proper 3 function. Each step of the myogenic process is regulated by specific regulatory factors including extrinsic cues, yet the nature and source of these signals remain unclear. This review will address these issues and discuss the different experimental models used to investigate the regenerative process. Prenatal and postnatal skeletal muscle developmentIn amniotes, skeletal muscles in the limbs and trunk arise from somites through a series of successive waves that include embryonic and foetal phases of myoblast production (Biressi et al., 2007;Comai and Tajbakhsh, 201...

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“…Here we show that PDGFRα signaling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated. 10–13 We found that FAPs produce multiple transcriptional variants of PDGFRα with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signaling and to prevent FAP over-activation.…”

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confidence: 99%

Intronic polyadenylation of PDGFRα in resident stem cells attenuates muscle fibrosis

Mueller

Velthoven

Fukumoto

et al. 2016

Nature

105

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The platelet-derived growth factor receptor alpha (PDGFRα) exhibits divergent effects in skeletal muscle. At physiological levels, signaling through this receptor promotes muscle development in growing embryos and proper angiogenesis in regenerating adult muscle.1,2 However, both increased PDGF ligand abundance and enhanced PDGFRα pathway activity cause pathological fibrosis.3,4 This excessive collagen deposition, which is seen in aged and diseased muscle,5–7 interferes with proper muscle function and limits the effectiveness of gene- and cell-based therapies for muscle disorders.8,9 Although compelling evidence exists for the role of PDGFRα in fibrosis, little is known about the cells through which this pathway acts. Here we show that PDGFRα signaling regulates a population of muscle-resident fibro/adipogenic progenitors (FAPs) that play a supportive role in muscle regeneration but may also cause fibrosis when aberrantly regulated.10–13 We found that FAPs produce multiple transcriptional variants of PDGFRα with different polyadenylation sites, including an intronic variant that codes for a protein isoform containing a truncated kinase domain. This variant, upregulated during regeneration, acts as a decoy to inhibit PDGF signaling and to prevent FAP over-activation. Moreover, increasing expression of this isoform limits fibrosis in vivo, suggesting both biological relevance and therapeutic potential of modulating polyadenylation patterns in stem cell populations.

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Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration

Cited by 120 publications

References 29 publications

Regulation of muscle growth and regeneration by the immune system

Regulation of muscle growth and regeneration by the immune system

Regulation and phylogeny of skeletal muscle regeneration

Intronic polyadenylation of PDGFRα in resident stem cells attenuates muscle fibrosis

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