transforming-growth-factor-alpha and Spinal-Cord-Injuries

Astrocytes are both detrimental and beneficial for repair and recovery after spinal cord injury (SCI). These dynamic cells are primary contributors to the growth-inhibitory glial scar, yet they are also neuroprotective and can form growth-supportive bridges on which axons traverse. We have shown that intrathecal administration of transforming growth factor α (TGFα) to the contused mouse spinal cord can enhance astrocyte infiltration and axonal growth within the injury site, but the mechanisms of these effects are not well understood. The present studies demonstrate that the epidermal growth factor receptor (EGFR) is upregulated primarily by astrocytes and glial progenitors early after SCI. TGFα directly activates the EGFR on these cells in vitro, inducing their proliferation, migration, and transformation to a phenotype that supports robust neurite outgrowth. Overexpression of TGFα in vivo by intraparenchymal adeno-associated virus injection adjacent to the injury site enhances cell proliferation, alters astrocyte distribution, and facilitates increased axonal penetration at the rostral lesion border. To determine whether endogenous EGFR activation is required after injury, SCI was also performed on Velvet (C57BL/6J-Egfr(Vel)/J) mice, a mutant strain with defective EGFR activity. The affected mice exhibited malformed glial borders, larger lesions, and impaired recovery of function, indicating that intrinsic EGFR activation is necessary for neuroprotection and normal glial scar formation after SCI. By further stimulating precursor proliferation and modifying glial activation to promote a growth-permissive environment, controlled stimulation of EGFR at the lesion border may be considered in the context of future strategies to enhance endogenous cellular repair after injury.

Topics: Analysis of Variance; Animals; Astrocytes; Axons; Bromodeoxyuridine; Cell Movement; Cell Proliferation; Cell Transdifferentiation; Cells, Cultured; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; ErbB Receptors; Female; Ganglia, Spinal; Glial Fibrillary Acidic Protein; Green Fluorescent Proteins; Humans; Lamins; Locomotion; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural Stem Cells; Neurofilament Proteins; Phenotype; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Transfection; Transforming Growth Factor alpha; Up-Regulation

Astrocytes respond to environmental cues and play a multifaceted role in the response to trauma in the central nervous system. As the most prevalent contributors to the glial scar, astrocytes are targeted as barriers to regeneration. However, there is also strong evidence that astrocytes are vital for neuroprotection and metabolic support after injury. In addition, consistent with their role during development, astrocytes may be capable of supporting the growth of injured axons. Therefore, we hypothesized that with appropriate stimulation, the reparative functions of endogenous astrocytes could be harnessed to promote axon growth and recovery after spinal cord injury. Transforming growth factor-alpha (TGF-alpha) is a mitogenic growth factor that is active on astrocytes and is poised to contribute to such a strategy. Recombinant TGF-alpha was administered intrathecally to adult C57BL/6 mice for two weeks following a moderate mid-thoracic spinal cord contusion. By three weeks post-injury, TGF-alpha infusion had not affected locomotor recovery, but promoted extensive axon growth and altered the composition of the lesion site. The center of the lesion in the treated mice contained greater numbers of new cells and increased astrocyte invasion. Despite the expression of inhibitory proteoglycans, there was a marked increase in axons expressing neurofilament and GAP-43 immunoreactivity, and the new axons were closely associated with increased laminin expression within and beyond the astrocyte matrix. The results demonstrate that astrocytes are dynamic players in the response to spinal cord injury, and the growth-supportive role of these cells can be enhanced by TGF-alpha infusion.

Topics: Analysis of Variance; Animals; Astrocytes; Axons; Cell Count; Female; Immunohistochemistry; Injections, Spinal; Mice; Microscopy, Confocal; Motor Activity; Nerve Regeneration; Random Allocation; Recovery of Function; Spinal Cord Injuries; Thoracic Vertebrae; Transforming Growth Factor alpha