Tenogenic Contribution to Skeletal Muscle Regeneration: The Secretome of Scleraxis Overexpressing Mesenchymal Stem Cells Enhances Myogenic Differentiation In Vitro

• Published in: International journal of molecular sciences Vol. 21; no. 6; p. 1965
• Main Authors: Strenzke, Maximilian, Alberton, Paolo, Aszodi, Attila, Docheva, Denitsa, Haas, Elisabeth, Kammerlander, Christian, Böcker, Wolfgang, Saller, Maximilian Michael
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13.03.2020; MDPI
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Bones; Cell adhesion & migration; Cell Differentiation; Cell Line; Cell Movement; Cells, Cultured; Contraction; Cytokines; Extracellular matrix; Fibroblasts; Gene expression; Genes; Growth factors; Homeostasis; Humans; Influence; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - metabolism; Metabolism; Mice; Morphology; Muscle contraction; Muscle Development; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - metabolism; Muscle Fibers, Skeletal - physiology; Muscles; Musculoskeletal system; Myoblasts; myotendinous junction; regenerative medicine; rna-seq; satellite cell; scleraxis; Secretome; Skeletal muscle; Stem cells; tendon-muscle crosstalk; Tendons; Tenocytes - metabolism; Transcription factors; Transcriptome; Tumor necrosis factor-TNF; satellite cell; RNA-Seq; mesenchymal stem cells; regenerative medicine; myotendinous junction; tendon-muscle crosstalk; scleraxis; skeletal muscle
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21061965

Integrity of the musculoskeletal system is essential for the transfer of muscular contraction force to the associated bones. Tendons and skeletal muscles intertwine, but on a cellular level, the myotendinous junctions (MTJs) display a sharp transition zone with a highly specific molecular adaption. The function of MTJs could go beyond a mere structural role and might include homeostasis of this musculoskeletal tissue compound, thus also being involved in skeletal muscle regeneration. Repair processes recapitulate several developmental mechanisms, and as myotendinous interaction does occur already during development, MTJs could likewise contribute to muscle regeneration. Recent studies identified tendon-related, scleraxis-expressing cells that reside in close proximity to the MTJs and the muscle belly. As the muscle-specific function of these scleraxis positive cells is unknown, we compared the influence of two immortalized mesenchymal stem cell (MSC) lines-differing only by the overexpression of scleraxis-on myoblasts morphology, metabolism, migration, fusion, and alignment. Our results revealed a significant increase in myoblast fusion and metabolic activity when exposed to the secretome derived from scleraxis-overexpressing MSCs. However, we found no significant changes in myoblast migration and myofiber alignment. Further analysis of differentially expressed genes between native MSCs and scleraxis-overexpressing MSCs by RNA sequencing unraveled potential candidate genes, i.e., extracellular matrix (ECM) proteins, transmembrane receptors, or proteases that might enhance myoblast fusion. Our results suggest that musculotendinous interaction is essential for the development and healing of skeletal muscles.