Eph/ephrin interactions modulate muscle satellite cell motility and patterning

Abstract

SUMMARYDuring development and regeneration, directed migration of cells, including neural crest cells, endothelial cells, axonal growth cones and many types of adult stem cells, to specific areas distant from their origin is necessary for their function. We have recently shown that adult skeletal muscle stem cells (satellite cells), once activated by isolation or injury, are a highly motile population with the potential to respond to multiple guidance cues, based on their expression of classical guidance receptors. We show here that, in vivo, differentiated and regenerating myofibers dynamically express a subset of ephrin guidance ligands, as well as Eph receptors. This expression has previously only been examined in the context of muscle-nerve interactions; however, we propose that it might also play a role in satellite cell-mediated muscle repair. Therefore, we investigated whether Eph-ephrin signaling would produce changes in satellite cell directional motility. Using a classical ephrin 'stripe' assay, we found that satellite cells respond to a subset of ephrins with repulsive behavior in vitro; patterning of differentiating myotubes is also parallel to ephrin stripes. This behavior can be replicated in a heterologous in vivo system, the hindbrain of the developing quail, in which neural crest cells are directed in streams to the branchial arches and to the forelimb of the developing quail, where presumptive limb myoblasts emigrate from the somite. We hypothesize that guidance signaling might impact multiple steps in muscle regeneration, including escape from the niche, directed migration to sites of injury, cell-cell interactions among satellite cell progeny, and differentiation and patterning of regenerated muscle.

Pharmacological targeting of the ephrin receptor kinase signalling by GLPG1790 in vitro and in vivo reverts oncophenotype, induces myogenic differentiation and radiosensitizes embryonal rhabdomyosarcoma cells

“…In line with this observation, GLPG1790 induced a significant up-regulation of MYOD1 and myogenin, followed by increased levels of MyHC protein, a marker of terminal myogenic differentiation, in both ERMS cell lines. The evidence that impairment of EPH-A2 is linked to myogenesis is in accordance with a report describing the role of EPH/Ephrin interactions in regulating the myogenic program at the expense of selfrenewal [36,37]. Contrarily to what expected, Cyclin D1 levels were rapidly and persistently increased by GLPG1790 treatment in comparison to mocked control cells.…”

Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy

“…Frozen muscle tissue was then cryosectioned at 20 μm per section. Immunohistochemistry was modified from a previously described protocol (36). Tissues were labeled using anti-laminin (1:250; catalog L9393, Sigma-Aldrich).…”

Satellite Cells and the Muscle Stem Cell Niche

“…Recently, sialomucin CD34, whose expression is high on quiescent satellite cells but dramatically reduced during satellite cell activation, was demonstrated to act as an antiadhesive molecule to facilitate migration and promote the proliferation of satellite cells at very early stages of muscle regeneration (8). In addition, dynamic regulation of Eph receptors and ephrin ligands in activated satellite cells and regenerating myofibers have been shown to direct satellite cell migration (506).…”