Interaction between mesenchymal stem cells and myoblasts in the context of facioscapulohumeral muscular dystrophy contributes to the disease phenotype

Ev, Kiseleva; Serbina, O.; Karpukhina, Anna; Mouly, Vincent; Vassetzky, Yegor S.

doi:10.1002/jcp.30789

Cited by 3 publications

(2 citation statements)

References 49 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…and presenting pro-fibrotic alterations [52]. A recent study furthermore demonstrated that FSHD myoblasts stimulate collagen secretion by mesenchymal stem cells [53]. In patients, MRI combined to a proteomic study of muscle interstitial fluid suggested defective muscle regeneration and increased fibrosis in early/active FSHD [49].…”

Section: Dux4c Protein Detection In Skeletal Muscle Is Associated Wit...mentioning

confidence: 99%

The double homeodomain protein DUX4c is associated with regenerating muscle fibers and RNA-binding proteins

et al. 2023

View full text Add to dashboard Cite

Background We have previously demonstrated that double homeobox 4 centromeric (DUX4C) encoded for a functional DUX4c protein upregulated in dystrophic skeletal muscles. Based on gain- and loss-of-function studies we have proposed DUX4c involvement in muscle regeneration. Here, we provide further evidence for such a role in skeletal muscles from patients affected with facioscapulohumeral muscular dystrophy (FSHD). Methods DUX4c was studied at RNA and protein levels in FSHD muscle cell cultures and biopsies. Its protein partners were co-purified and identified by mass spectrometry. Endogenous DUX4c was detected in FSHD muscle sections with either its partners or regeneration markers using co-immunofluorescence or in situ proximity ligation assay. Results We identified new alternatively spliced DUX4C transcripts and confirmed DUX4c immunodetection in rare FSHD muscle cells in primary culture. DUX4c was detected in nuclei, cytoplasm or at cell–cell contacts between myocytes and interacted sporadically with specific RNA-binding proteins involved, a.o., in muscle differentiation, repair, and mass maintenance. In FSHD muscle sections, DUX4c was found in fibers with unusual shape or central/delocalized nuclei (a regeneration feature) staining for developmental myosin heavy chain, MYOD or presenting intense desmin labeling. Some couples of myocytes/fibers locally exhibited peripheral DUX4c-positive areas that were very close to each other, but in distinct cells. MYOD or intense desmin staining at these locations suggested an imminent muscle cell fusion. We further demonstrated DUX4c interaction with its major protein partner, C1qBP, inside myocytes/myofibers that presented features of regeneration. On adjacent muscle sections, we could unexpectedly detect DUX4 (the FSHD causal protein) and its interaction with C1qBP in fusing myocytes/fibers. Conclusions DUX4c upregulation in FSHD muscles suggests it contributes not only to the pathology but also, based on its protein partners and specific markers, to attempts at muscle regeneration. The presence of both DUX4 and DUX4c in regenerating FSHD muscle cells suggests DUX4 could compete with normal DUX4c functions, thus explaining why skeletal muscle is particularly sensitive to DUX4 toxicity. Caution should be exerted with therapeutic agents aiming for DUX4 suppression because they might also repress the highly similar DUX4c and interfere with its physiological role. Graphical Abstract

show abstract

Section: Dux4c Protein Detection In Skeletal Muscle Is Associated Wit...mentioning

confidence: 99%

The double homeodomain protein DUX4c is associated with regenerating muscle fibers and RNA-binding proteins

et al. 2023

View full text Add to dashboard Cite

show abstract

“…As the unit's center, cells can sense and respond to mechanical signals by altering their biological activities and synthesizing or degrading the ECM, thus impacting tissue formation and maturation 21 , 22 . Many failed tissue or organ developments have been linked to construction unit dysfunction 23 , 24 . The cytoskeleton-ECM coupled with interactions is a critical axis through which signals are transduced from the extracellular space to the intracellular space 25 .…”

Section: Introductionmentioning

confidence: 99%

Upregulated desmin/integrin β1/MAPK axis promotes elastic cartilage regeneration with increased ECM mechanical strength

Zhang,

Lu,

et al. 2023

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Elastic cartilage tissue engineering is promising for providing available scaffolds for plastic reconstructive surgery. The insufficient mechanical strength of regenerative tissue and scarce resources of reparative cells are two obstacles for the preparation of tissue-engineered elastic cartilage scaffolds. Auricular chondrocytes are important reparative cells for elastic cartilage tissue engineering, but resources are scarce. Identifying auricular chondrocytes with enhanced capability of elastic cartilage formation is conducive to reducing the damage to donor sites by decreasing the demand on native tissue isolation. Based on the biochemical and biomechanical differences in native auricular cartilage, we found that auricular chondrocytes with upregulated desmin expressed more integrin β1, forming a stronger interaction with the substrate. Meanwhile, activated MAPK pathway was found in auricular chondrocytes highly expressing desmin. When desmin was knocked down, the chondrogenesis and mechanical sensitivity of chondrocytes were both impaired, and the MAPK pathway was downregulated. Finally, auricular chondrocytes highly expressing desmin regenerated more elastic cartilage with increased ECM mechanical strength. Therefore, desmin/integrin β1/MAPK signaling can not only serve as a selection standard but also a manipulation target of auricular chondrocytes to promote elastic cartilage regeneration.

show abstract

Interaction between mesenchymal stem cells and myoblasts in the context of facioscapulohumeral muscular dystrophy contributes to the disease phenotype

Serbina

Karpukhina

et al. 2022

Journal Cellular Physiology

View full text Add to dashboard Cite

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disease associated with ectopic expression of the DUX4 gene in skeletal muscle. Muscle degeneration in FSHD is accompanied by muscle tissue replacement with fat and connective tissue. Expression of DUX4 in myoblasts stimulates mesenchymal stem cells (MSC) migration via the CXCR4‐CXCL12 axis. MSCs participate in adipose and connective tissue formation and can contribute to fibrosis. Here we studied the interaction between myoblasts and MSCs and the consequences of this interaction in the FSHD context. We used cell motility assays and coculture of MSCs with myoblasts to study their mutual effects on cell migration, differentiation, proliferation, and extracellular matrix formation. The growth medium conditioned by FSHD myoblasts stimulated MSCs migration 1.6‐fold (p < 0.04) compared to nonconditioned medium. Blocking the CXCL12‐CXCR4 axis with the CXCR4 inhibitor (AMD3100) or neutralizing antibodies to CXCL12 abolished this effect. FSHD myoblasts stimulated MSC proliferation 1.5−2 times (p < 0.05) compared to control myoblasts, while the presence of MSCs impaired myoblast differentiation. Under inflammatory conditions, medium conditioned by FSHD myoblasts stimulated collagen secretion by MSCs 2.2‐fold as compared to the nonconditioned medium, p < 0.03. FSHD myoblasts attract MSCs via the CXCL12‐CXCR4 axis, stimulate MSC proliferation and collagen secretion by MSCs. Interaction between MSCs and FSHD myoblasts accounts for several important aspects of FSHD pathophysiology. The CXCL12‐CXCR4 axis may serve as a potential target to improve the state of the diseased muscles.

show abstract

Interaction between mesenchymal stem cells and myoblasts in the context of facioscapulohumeral muscular dystrophy contributes to the disease phenotype

Cited by 3 publications

References 49 publications

The double homeodomain protein DUX4c is associated with regenerating muscle fibers and RNA-binding proteins

The double homeodomain protein DUX4c is associated with regenerating muscle fibers and RNA-binding proteins

Upregulated desmin/integrin β1/MAPK axis promotes elastic cartilage regeneration with increased ECM mechanical strength

Interaction between mesenchymal stem cells and myoblasts in the context of facioscapulohumeral muscular dystrophy contributes to the disease phenotype

Contact Info

Product

Resources

About