Extracellular matrix and integrins influence in the regulation of myogenic precursor cells behaviour

Abstract

Myogenesis is the process by which undifferentiated dermomyotomal cells are specified for myogenesis, move towards the myotome where they differentiate into skeletal muscle cells that fuse into myotubes and later in development form myofibers which will constitute the skeletal muscles of the adult. The muscle precursor cells arise from the dermomyotome, an epithelial-like structure that is the source for skeletal muscle and dorsal dermis cells. Some cells, called satellite cells, go throughout part of this differentiation process but remain in a quiescent undifferentiated state (although committed to skeletal muscle fate). These cells are activated in the adult in case of muscle injury or enhanced exercise, for example. In this work we used a satellite cell-derived cell line, C2C12, and the mouse embryo to study the extracellular matrix (ECM) and integrins influence in myogenic determination and differentiation. Integrins are heterodimeric ECM receptors constituted by an α and a ß subunit that can induce, for example, migration or differentiation. The integrin ligand specificity is acquired by the combination of both subunits. Our studies have addressed that laminin-α6ß1 integrin interaction may be coordinating with Notch signaling the maintenance of undifferentiated dermomyotomal cells. By inhibiting Notch signaling, we observed precocious myogenic differentiation of dermomyotomal cells (by Myf5 expression) and the assembly of a laminin matrix around these cells. This result suggests that Myf5 induces laminin assembly. In vitro, fibronectin enhances C2C12 myoblasts alignment and migration. When we observed the myotubes of cells grown on fibronectin, we believe that the enhanced cell alignment imposed by fibronectin-α5ß1 integrin interaction will facilitate cell fusion. In vivo, we found that fibronectin is important for dermomyotome epithelial-integrity, especially through the polarization of N-cadherin, and that α5ß1 integrin signaling may also contribute to myogenic repression in the dermomyotome. These observations show that the ECM and integrins are of paramount importance in myoblast cell behaviour.

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