TIMP3 Attenuates the Loss of Neural Stem Cells, Mature Neurons and Neurocognitive Dysfunction in Traumatic Brain Injury. (23rd October 2015)

• Record Type: Journal Article
• Authors: Gibb, Stuart L.; Zhao, Yuhai; Potter, Daniel; Hylin, Michael J.; Bruhn, Roberta; Baimukanova, Gyulnar; Zhao, Jing; Xue, Hasen; Abdel-Mohsen, Mohamed; Pillai, Satish K.; Moore, Anthony N.; Johnson, Evan M.; Cox, Charles S.; Dash, Pramod K.; Pati, Shibani
• Is Part Of: Stem cells. Volume 33:Number 12(2015:Dec.)
• Page Start: 3530
• Page End: 3544
• Publication Date: 2015-10-23
• Subjects: Tissue inhibitor of matrix metalloproteinase-3 -- Mesenchymal stem cell -- Neural stem cell -- Traumatic brain injury -- Hippocampus; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2189
• Languages: English
• ISSNs: 1066-5099

Abstract

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. Stem Cells 2015;33:3530–3544