TIMP3 Attenuates the Loss of Neural Stem Cells, Mature Neurons and Neurocognitive Dysfunction in Traumatic Brain Injury

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 metallo...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2015-12, Vol.33 (12), p.3530-3544
Main 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
Format: Article
Language:English
Subjects:
Animals
Bone marrow
Brain Injuries - drug therapy
Brain Injuries - metabolism
Brain Injuries - pathology
Brain Injuries - physiopathology
Cognition Disorders - drug therapy
Cognition Disorders - metabolism
Cognition Disorders - pathology
Hippocampus
Hippocampus - metabolism
Hippocampus - pathology
Mesenchymal stem cell
Mice
Neural stem cell
Neural Stem Cells - metabolism
Neural Stem Cells - pathology
Neurons
Neurons - metabolism
Neurons - pathology
Stem cells
Tissue inhibitor of matrix metalloproteinase‐3
Tissue Inhibitor of Metalloproteinase-3 - pharmacology
Traumatic brain injury
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Summary: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
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.2189