title: Biophysical stimulation induces demyelination via an integrin-dependent mechanism.
abstract: OBJECTIVE
  Chronic nerve compression (CNC) injuries occur when peripheral nerves are subjected to sustained mechanical forces, with increasing evidence implicating Schwann cells as key mediators. Integrins, a family of transmembrane adhesion molecules that are capable of intracellular signaling, have been implicated in a variety of biological processes such as myelination and nerve regeneration. In this study, we seek to define the physical stimuli mediating demyelination and to determine whether integrin plays a role in the demyelinating response.
  
  
  METHODS
  We used a previously described in vitro model of CNC injury where myelinating neuron-Schwann cell cocultures were subjected to independent manipulations of hydrostatic pressure, hypoxia, and glucose deprivation in a custom bioreactor. We assessed whether demyelination increased in response to applied manipulation and determined whether integrin-associated signaling cascades are upregulated.
  
  
  RESULTS
  Biophysical stimulation of neural tissue induced demyelination and Schwann cell proliferation without neuronal or glial cytotoxicity or apoptosis. Although glucose deprivation and hypoxia independently had minor effects on myelin stability, together they potentiated the demyelinating effects of hydrostatic compression, and in combination, significantly destabilized myelin. Biophysical stimuli transiently increased phosphorylation of the integrin-associated tyrosine kinase Src within Schwann cells. Silencing this integrin signaling cascade blocked Src activation and prevented pressure-induced demyelination. Colocalization analysis indicated that Src is localized within Schwann cells.
  
  
  CONCLUSIONS
  These results indicate that myelin is sensitive to CNC injury and support the novel concept that myelinating cocultures respond directly to mechanical loading via activating an integrin signaling cascade.
authors: Department of Orthopedic Surgery, University of California, Irvine, USA.
authors: Michael Y
authors: MY
authors: Lin
authors: Laura S
authors: LS
authors: Frieboes
authors: Maryam
authors: M
authors: Forootan
authors: Winnie A
authors: WA
authors: Palispis
authors: Tahseen
authors: T
authors: Mozaffar
authors: Matiar
authors: M
authors: Jafari
authors: Oswald
authors: O
authors: Steward
authors: Christine M
authors: CM
authors: Gall
authors: Ranjan
authors: R
authors: Gupta
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D049109:Cell Proliferation; D018920:Coculture Techniques; D003711:Demyelinating Diseases / Q000378:metabolism* / Q000473:pathology; D005727:Ganglia, Spinal / Q000378:metabolism / Q000473:pathology; D016023:Integrins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism* / Q000473:pathology; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016023:Integrins