Extracellular matrix remodeling in the injured spinal cord: a novel mechanism partially repairing mature CNS

Mark van der Vlies^1,2, Deniz Konya^1,2, Amanda F. Mower³, Rajiv Saigal^1,4, Dou Yu^1,2, Paul M. George^3,4, Jianxue Li⁵, Richard L. Sidman⁵, Mriganka Sur³ and Yang D. Teng^1,2

¹Department of Neurosurgery, Harvard Medical School, Brigham and Women’s Hospital and Children’s and Service, Veterans Affairs Boston Healthcare System, West Roxbury, Massachusetts 02132

³Department of Brain and Cognitive Sciences and Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, 02139

⁴Harvard-MIT Division of Health Sciences and Technology, and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139

⁵Department of Neurology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115,

Recent research on neurotrauma and neuroregeneration points to up-regulation of developmental molecular components in the post-insult adult CNS, and suggests that rejuvenation of a microenvironment permissive for neuroplasticity may be an effective strategy for functional repair. We previously reported that critical period plasticity in visual cortical synaptic organization can be modified via remodeling of extracellular matrix (ECM) constituents by the tPA/plasmin proteolytic cascade (Oray, Majewska & Sur: Neuron 2004, 44:1021). Here we propose that a similar mechanism may be critical in the recovery process after spinal cord injury. To test our hypothesis, ECM remodeling in the post-lesion spinal cord was activated by local delivery of tPA into the cord parenchyma adjacent to the injury epicenter 3 d after contusion. This treatment elevated immunoreactivity levels of neurofilament-M and GAP-43 markers associated with neurites and their outgrowth/sprouting in the remaining cord. We also found that compared to control vehicle microinfusion, tPA treatment significantly increased the presence scale of synapsin, a protein which binds synaptic vesicles to regulate neurotransmitter release. Importantly, the number of descending serotonin-immunoreactive axons, mediating primary motofunction, was markedly higher in the tPA-treated spinal cord compared with controls. Also, tPA-increased corticospinal tract sprouting/regeneration was prominent. Thus, neuroregeneration and tissue repair in the post-developmental CNS can be facilitated by elevating levels of ECM remodeling factors that promote neuroplasticity.