Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

Charrin, Stéphanie; Latil, Mathilde; Soave, Sabrina; Polesskaya, Anna; Chrétien, Fabrice; Boucheix, Claude; Rubinstein, Eric

doi:10.1038/ncomms2675

Cited by 76 publications

(67 citation statements)

References 49 publications

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“…The shape of the egg microvilli are also altered in the absence of CD9 (Runge et al, 2007). Furthermore, CD9 and CD81 cooperate in macrophage fusion and muscle cell fusion, but as negative regulators of these processes (Charrin et al, 2013;Takeda et al, 2003). The increased muscle cell fusion observed in their absence has been recapitulated by RNA interference (RNAi)-mediated depletion of CD9P-1, pointing again to the importance of tetraspaninassociated molecules (Charrin et al, 2013).…”

Section: The Regulation Of Integrin Function By Cd151 and Other Tetramentioning

confidence: 63%

“…Furthermore, CD9 and CD81 cooperate in macrophage fusion and muscle cell fusion, but as negative regulators of these processes (Charrin et al, 2013;Takeda et al, 2003). The increased muscle cell fusion observed in their absence has been recapitulated by RNA interference (RNAi)-mediated depletion of CD9P-1, pointing again to the importance of tetraspaninassociated molecules (Charrin et al, 2013). Finally, double CD9 CD81 knockout mice also display a number of pathologies that are not, or only minimally, observed in single-mutant mice, such as pulmonary emphysema (a major pathological component of chronic obstructive pulmonary disease) (Takeda et al, 2008), osteopenia (Takeda et al, 2008) or defects of blood and lymphatic vessels (Iwasaki et al, 2013).…”

Section: The Regulation Of Integrin Function By Cd151 and Other Tetramentioning

confidence: 99%

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Tetraspanins at a glance

Charrin

Jouannet

Boucheix

et al. 2014

Journal of Cell Science

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356

371

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Tetraspanins are a family of proteins with four transmembrane domains that play a role in many aspects of cell biology and physiology; they are also used by several pathogens for infection and regulate cancer progression. Many tetraspanins associate specifically and directly with a limited number of proteins, and also with other tetraspanins, thereby generating a hierarchical network of interactions. Through these interactions, tetraspanins are believed to have a role in cell and membrane compartmentalization. In this Cell Science at a Glance article and the accompanying poster, we describe the basic principles underlying tetraspaninbased assemblies and highlight examples of how tetraspanins regulate the trafficking and function of their partner proteins that are required for the normal development and function of several organs, including, in humans, the eye, the kidney and the immune system.

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Section: The Regulation Of Integrin Function By Cd151 and Other Tetramentioning

confidence: 63%

Section: The Regulation Of Integrin Function By Cd151 and Other Tetramentioning

confidence: 99%

Tetraspanins at a glance

Charrin

Jouannet

Boucheix

et al. 2014

Journal of Cell Science

Self Cite

356

371

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“…Impaired tissue repair has been linked to compromised chemotaxis [24], vascularization [22,23], and cell fusion [26] in CD9 2/2 mice [40][41][42]. In addition to these phenotypes, exosome release is reduced in these mice [31,32].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model

Furuta

Miyaki

Ishitobi

et al. 2016

Stem Cells Translational Medicine

347

362

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Paracrine signaling by bone-marrow-derived mesenchymal stem cells (MSCs) plays a major role in tissue repair. Although the production of regulatory cytokines by MSC transplantation is a critical modulator of tissue regeneration, we focused on exosomes, which are extracellular vesicles that contain proteins and nucleic acids, as a novel additional modulator of cell-to-cell communication and tissue regeneration. To address this, we used radiologic imaging, histological examination, and immunohistochemical analysis to evaluate the role of exosomes isolated from MSC-conditioned medium (CM) in the healing process in a femur fracture model of CD9 2/2 mice, a strain that is known to produce reduced levels of exosomes. We found that the bone union rate in CD9 2/2 mice was significantly lower than wild-type mice because of the retardation of callus formation. The retardation of fracture healing in CD9 2/2 mice was rescued by the injection of exosomes, but this was not the case after the injection of exosomes-free conditioned medium (CM-Exo). The levels of the bone repairrelated cytokines, monocyte chemotactic protein-1 (MCP-1), MCP-3, and stromal cell-derived factor-1 in exosomes were low compared with levels in CM and CM-Exo, suggesting that bone repair may be in part mediated by other exosome components, such as microRNAs. These results suggest that exosomes in CM facilitate the acceleration of fracture healing, and we conclude that exosomes are a novel factor of MSC paracrine signaling with an important role in the tissue repair process. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1620-1630 SIGNIFICANCEThis work focuses on exosomes, which are extracellular vesicles, as a novel additional modulator of cell-to-cell communication. This study evaluated the role of exosomes isolated from mesenchymal stem cell (MSC)-conditioned medium (MSC-CM) in the fracture-healing process of CD9 2/2 mice, a strain that is known to produce reduced levels of exosomes. Retardation of fracture healing in CD9 2/2 mice was rescued by the injection of MSC exosomes, but this was not the case after the injection of exosome-free CM. This study finds that MSC exosomes are a novel factor of MSC paracrine signaling, with an important role in the tissue repair process.

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“…CD9 upregulation may explain the abnormal distribution of the nuclei observed in LGMD2A myotubes given that normal muscle regeneration requires a tight control of myoblast fusion by the tetraspanins CD9 and CD81 (Ref. 26).…”

Section: Discussionmentioning

confidence: 99%

FRZB and melusin, overexpressed in LGMD2A, regulate integrin β1D isoform replacement altering myoblast fusion and the integrin-signalling pathway

Jaka

Casas-Fraile

Azpitarte

et al. 2017

Expert Rev. Mol. Med.

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Limb-girdle muscular dystrophy type 2A (LGMD2A) is characterised by muscle wasting and progressive degeneration of proximal muscles because of mutations in the CAPN3 gene. However, the underlying pathophysiological mechanisms of muscle degeneration are still not well understood. The objective of this study was to assess the relevance of genes with differential expression in the muscle of LGMD2A patients. For this purpose, we analysed their in vitro expression in primary cultures of human myoblasts and myotubes. Abnormal fusion was observed in the myotubes of these patients, which may be explained by the lack of physiological replacement of integrin β1D. Owing to this observation, we focused on deregulated genes coding proteins that directly interact with integrin, ITGB1BP2 and CD9, as well as FRZB gene, because of its in vitro upregulation in myotubes. Silencing studies established that these genes are closely regulated, CD9 and FRZB being positive regulators of the expression of ITGB1BP2, and in turn, this gene being a negative regulator of the expression of FRZB. Interestingly, we observed that FRZB regulates integrin β1D expression, its silencing increasing integrin β1D expression to levels similar to those in controls. Finally, the administration of LiCl, an enhancer of the Wnt-signalling pathway showed similar experimentally beneficial effects, suggesting FRZB silencing or LiCl administration as potential therapeutic targets, though further studies are required.

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Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

Cited by 76 publications

References 49 publications

Tetraspanins at a glance

Tetraspanins at a glance

Mesenchymal Stem Cell-Derived Exosomes Promote Fracture Healing in a Mouse Model

FRZB and melusin, overexpressed in LGMD2A, regulate integrin β1D isoform replacement altering myoblast fusion and the integrin-signalling pathway

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