Matrix metalloproteinase-9 facilitates glial scar formation in the injured spinal cord.
In the injured spinal cord, a glial scar forms and becomes a major obstacle to axonal regeneration. Formation of the glial scar involves migration of astrocytes toward the lesion. Matrix metalloproteinases (MMPs), including MMP-9 and MMP-2, govern cell migration through their ability to degrade constituents of the extracellular matrix. Although MMP-9 is expressed in reactive astrocytes, its involvement in astrocyte migration and formation of a glial scar is unknown. Here we found that spinal cord injured, wild-type mice expressing MMPs developed a more severe glial scar and enhanced expression of chondroitin sulfate proteoglycans, indicative of a more inhibitory environment for axonal regeneration/plasticity, than MMP-9 null mice. To determine whether MMP-9 mediates astrocyte migration, we conducted a scratch wound assay using astrocytes cultured from MMP-9 null, MMP-2 null, and wild-type mice. Gelatin zymography confirmed the expression of MMP-9 and MMP-2 in wild-type cultures. MMP-9 null astrocytes and wild-type astrocytes, treated with an MMP-9 inhibitor, exhibited impaired migration relative to untreated wild-type controls. MMP-9 null astrocytes showed abnormalities in the actin cytoskeletal organization and function but no detectable untoward effects on proliferation, cellular viability, or adhesion. Interestingly, MMP-2 null astrocytes showed increased migration, which could be attenuated in the presence of an MMP-9 inhibitor. Collectively, our studies provide explicit evidence that MMP-9 is integral to the formation of an inhibitory glial scar and cytoskeleton-mediated astrocyte migration. MMP-9 may thus be a promising therapeutic target to reduce glial scarring during wound healing after spinal cord injury.
Hsu
Jung-Yu C
JY
Department of Neurological Surgery, University of California, San Francisco, California 94143, USA. jungyu.hsu@gmail.com
Bourguignon
Lilly Y W
LY
Adams
Christen M
CM
Peyrollier
Karine
K
Zhang
Haoqian
H
Fandel
Thomas
T
Cun
Christine L
CL
Werb
Zena
Z
Noble-Haeusslein
Linda J
LJ
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology*; D013119:Spinal Cord Injuries / Q000201:enzymology / Q000473:pathology*
D000199:Actins; D011508:Chondroitin Sulfate Proteoglycans; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9