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. STEM CELLS 2015;33:3530-3544 SIGNIFICANCE STATEMENTTBI is the main cause of death worldwide in ages 1-44 with few if any effective therapeutic options to treat patients. Our data suggest that TIMP3, a protein released by Mesenchymal Stem Cells may be a worthy therapeutic candidate. We report that TIMP3 has direct and potent effects on neuronal survival and neurocognitive function post TBI. This study builds upon our previous work that showed TIMP3 is protective against blood brain barrier compromise in the disease. Our findings report a critical role of the Akt-mTORC1 pathway and that inhibition of this pathway abrogates the neuroprotective effect of TIMP3.

Concise Review: Mesenchymal Stem (Stromal) Cells: Biology and Preclinical Evidence for Therapeutic Potential for Organ Dysfunction Following Trauma or Sepsis

“…There are similarities between MAPC and MSC but there do not appear to be any rigorous comparisons of the two cell types that identify their differences . Interestingly, when MSC are administered intravenously, they are initially trapped in the pulmonary circulation through a first pass effect for several hours and the beneficial effects on the injured brain occurs through release of paracrine factors, such as TSG‐6 and TIMP‐3 and HGF, rather than direct migration and differentiation of the MSC to the brain . The potential role of microvesicles released by MSC has also been studied in experimental models of TBI, and demonstrated that microvesicles and exosomes may well also play a role in reducing experimental brain injury .…”

Preclinical progenitor cell therapy in traumatic brain injury: a meta-analysis

“…To that end some investigators are working with modified progenitor cells that are being reprogrammed to over-express certain factors secreted by progenitor cells, and some groups are directly injecting the factors themselves (such as TIMP3 or Wnt3a) (74, 76). As this research progresses the mechanism or mechanisms of action will be more fully understood, and cellular therapies can be better harnessed and used to the best benefit.…”

Wnt3a, a Protein Secreted by Mesenchymal Stem Cells Is Neuroprotective and Promotes Neurocognitive Recovery Following Traumatic Brain Injury

“…Studies have shown that both mature neurons and newborn neurons are vulnerable to TBI. Up to 80% of doublecortin‐positive (DCX+) neural stem cells are lost following moderate‐to‐severe TBI . In addition, newly generated neurons from hippocampal neurogenesis are thought to play critical roles in certain types of learning and memory .…”