title: Mesenchymal stem cells regulate blood-brain barrier integrity through TIMP3 release after traumatic brain injury.
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.
authors.affiliation: Blood Systems Research Institute, San Francisco, CA 94118, USA.
authors.forename: Tyler
authors.initials: T
authors.lastname: Menge
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Zhao
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Kathryn
authors.initials: K
authors.lastname: Wataha
authors.forename: Michael
authors.initials: M
authors.lastname: Gerber
authors.forename: Jianhu
authors.initials: J
authors.lastname: Zhang
authors.forename: Phillip
authors.initials: P
authors.lastname: Letourneau
authors.forename: John
authors.initials: J
authors.lastname: Redell
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Zhalong
authors.initials: Z
authors.lastname: Peng
authors.forename: Hasen
authors.initials: H
authors.lastname: Xue
authors.forename: Rosemary
authors.initials: R
authors.lastname: Kozar
authors.forename: Charles S
authors.initials: CS
authors.lastname: Cox
authors.forename: Aarif Y
authors.initials: AY
authors.lastname: Khakoo
authors.forename: John B
authors.initials: JB
authors.lastname: Holcomb
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Dash
authors.forename: Shibani
authors.initials: S
authors.lastname: Pati
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism / Q000473:pathology; D061605:Administration, Intravenous; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D001930:Brain Injuries / Q000097:blood / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000097:blood / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D019717:Tissue Inhibitor of Metalloproteinase-3