Mesenchymal stem cells regulate blood-brain barrier integrity through TIMP3 release after traumatic brain injury

• Published in: Science translational medicine 2012-11, Vol.4 (161), p.161ra150-161ra150
• Main Authors: Menge, Tyler, Zhao, Yuhai, Zhao, Jing, Wataha, Kathryn, Gerber, Michael, Zhang, Jianhu, Letourneau, Phillip, Redell, John, Shen, Li, Wang, Jing, Peng, Zhalong, Xue, Hasen, Kozar, Rosemary, Cox, Jr, Charles S, Khakoo, Aarif Y, Holcomb, John B, Dash, Pramod K, Pati, Shibani
• Format: Article
• Language: English
• Subjects: Adherens Junctions - metabolism; Adherens Junctions - pathology; Administration, Intravenous; Animals; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain - blood supply; Brain - drug effects; Brain - pathology; Brain Injuries - blood; Brain Injuries - metabolism; Brain Injuries - pathology; Brain Injuries - therapy; Coculture Techniques; Disease Models, Animal; Down-Regulation; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Gene Knockdown Techniques; Humans; Liver - drug effects; Liver - metabolism; Lung - drug effects; Lung - metabolism; Lung - pathology; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mice; Neutrophil Infiltration - drug effects; Recombinant Proteins - pharmacology; RNA, Small Interfering - metabolism; Spleen - drug effects; Spleen - metabolism; Tissue Inhibitor of Metalloproteinase-3 - blood; Tissue Inhibitor of Metalloproteinase-3 - metabolism
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.3004660

Mesenchymal stem cells (MSCs) may be useful for treating a variety of disease states associated with vascular instability including traumatic brain injury (TBI). A soluble factor, tissue inhibitor of matrix metalloproteinase-3 (TIMP3), produced by MSCs is shown to recapitulate the beneficial effects of MSCs on endothelial function and to ameliorate the effects of a compromised blood-brain barrier (BBB) due to TBI. Intravenous administration of recombinant TIMP3 inhibited BBB permeability caused by TBI, whereas attenuation of TIMP3 expression in intravenously administered MSCs blocked the beneficial effects of the MSCs on BBB permeability and stability. MSCs increased circulating concentrations of soluble TIMP3, which blocked vascular endothelial growth factor-A-induced breakdown of endothelial cell adherens junctions in vitro and in vivo. These findings elucidate a potential molecular mechanism for the beneficial effects of MSCs on the BBB after TBI and demonstrate a role for TIMP3 in the regulation of BBB integrity.