title: TIMP3 Attenuates the Loss of Neural Stem Cells, Mature Neurons and Neurocognitive Dysfunction in Traumatic Brain Injury.
abstract: Mesenchymal stem cells (MSCs) have been shown to have potent therapeutic effects in a number of disorders including traumatic brain injury (TBI). However, the molecular mechanism(s) underlying these protective effects are largely unknown. Herein we demonstrate that tissue inhibitor of matrix metalloproteinase-3 (TIMP3), a soluble protein released by MSCs, is neuroprotective and enhances neuronal survival and neurite outgrowth in vitro. In vivo in a murine model of TBI, intravenous recombinant TIMP3 enhances dendritic outgrowth and abrogates loss of hippocampal neural stem cells and mature neurons. Mechanistically we demonstrate in vitro and in vivo that TIMP3-mediated neuroprotection is critically dependent on activation of the Akt-mTORC1 pathway. In support of the neuroprotective effect of TIMP3, we find that intravenous delivery of recombinant TIMP3 attenuates deficits in hippocampal-dependent neurocognition. Taken together, our data strongly suggest that TIMP3 has direct neuroprotective effects that can mitigate the deleterious effects associated with TBI, an area with few if any therapeutic options.
authors: Blood Systems Research Institute, San Francisco, California, USA.|Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors: Stuart L
authors: SL
authors: Gibb
authors: Department of Neurobiology and Anatomy, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
authors: Yuhai
authors: Y
authors: Zhao
authors: Blood Systems Research Institute, San Francisco, California, USA.|Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors: Daniel
authors: D
authors: Potter
authors: Department of Neurobiology and Anatomy, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
authors: Michael J
authors: MJ
authors: Hylin
authors: Blood Systems Research Institute, San Francisco, California, USA.|Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors: Roberta
authors: R
authors: Bruhn
authors: Blood Systems Research Institute, San Francisco, California, USA.|Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors: Gyulnar
authors: G
authors: Baimukanova
authors: Department of Neurobiology and Anatomy, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
authors: Jing
authors: J
authors: Zhao
authors: Department of Pediatric Surgery and Institute for Molecular Medicine, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
authors: Hasen
authors: H
authors: Xue
authors: Blood Systems Research Institute, San Francisco, California, USA.|Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors: Mohamed
authors: M
authors: Abdel-Mohsen
authors: Blood Systems Research Institute, San Francisco, California, USA.|Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors: Satish K
authors: SK
authors: Pillai
authors: Department of Neurobiology and Anatomy, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
authors: Anthony N
authors: AN
authors: Moore
authors: Department of Neurobiology and Anatomy, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
authors: Evan M
authors: EM
authors: Johnson
authors: Department of Pediatric Surgery and Institute for Molecular Medicine, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
authors: Charles S
authors: CS
authors: Cox
authors: Department of Neurobiology and Anatomy, The University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
authors: Pramod K
authors: PK
authors: Dash
authors: Blood Systems Research Institute, San Francisco, California, USA.|Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
authors: Shibani
authors: S
authors: Pati
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000494:pharmacology*
chemical_list: D019717:Tissue Inhibitor of Metalloproteinase-3
keywords: Hippocampus; Mesenchymal stem cell; Neural stem cell; Tissue inhibitor of matrix metalloproteinase-3; Traumatic brain injury