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

Tyler Menge, Yuhai Zhao, Jing Zhao, Kathryn Wataha, Michael Gerber, Jianhu Zhang, Phillip Letourneau, John Redell, Li Shen, Jing Wang, Zhalong Peng, Hasen Xue, Rosemary Kozar, Charles S. Cox, Aarif Y. Khakoo, John B. Holcomb, Pramod K. Dash, Shibani Pati

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number161ra150
JournalScience translational medicine
Volume4
Issue number161
DOIs
StatePublished - Nov 21 2012
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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