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Studying MSC-Based Neuroprotection to Generate Cell-Free Therapies?

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Review of “TIMP3 Attenuates the Loss of Neural Stem Cells, Mature Neurons, and Neurocognitive Dysfunction in Traumatic Brain Injury” from Stem Cells by Stuart P. Atkinson

The transplantation of stem cells and their derivatives is being investigated far and wide as a therapy for a range of various diseases and disorders. However, if we can begin to understand just how stem cells effect their reparative/regenerative function we can begin to construct safer, cell-free, and defined therapeutic strategies. This is particularly relevant to the application of mesenchymal stem cells (MSCs) which appear to mainly function through paracrine mechanisms via secreted factors.

The laboratory of Shibani Pati (Blood Systems Research Institute, San Francisco) has previously reported on the positive therapeutic consequences of MSCs treatment in the long-term consequences of traumatic brain injury (TBI) [1, 2]. In their new report, published in Stem Cells, they now show that TIMP3 (tissue inhibitor of matrix metalloproteinase-3) release by MSCs has a potent and direct neuroprotective effect and can reduce neurocognitive decline in a mouse model of TBI [3].

Their previous studies found that TIMP3 had a beneficial effect on blood-brain-barrier (BBB) permeability after TBI [1, 2], and in this new study, they extended these findings to show that MSC-derived TIMP3 could penetrate into the dentate gyrus of the hippocampus. There it inhibited the loss of post-mitotic neurons and neural stem cells (NSCs) and so prevented the neurocognitive decline normally observed in a murine model of controlled cortical impact (CCI)-induced TBI. Mechanistically, both in vitro and in vivo analyses found that TIMP3 could potentiate the Akt-mTORC1 signaling pathway to phosphorylate and activate the S6 ribosomal protein (S6RP) (See Figure) which can promote protein synthesis and is known to mediate axon regeneration following injury [4].

Indeed, the authors found that the TIMP3 mediated-activation of Akt-mTORC1 signaling coincided with increased neuron survival and outgrowth of neurites in vitro and the preservation of the hippocampal neural cytoskeletal morphology and circuitry in vivo following TBI. Encouragingly, the effect of TIMP3 was so potent that treatment significantly attenuated hippocampal-dependent neurocognitive decline following TBI, as demonstrated by improvements in spatial learning, memory, and context-dependent fear discrimination.

This exciting study will hopefully represent another step closer to an effective cell-free intravenously delivered treatment for the shattering after-effects of TBI. The authors note that such an advance is much needed given that many clinical trials for TBI treatments have failed to advance [5], leaving TBI with a high unmet medical need.

References

  1. Menge T, Zhao Y, Zhao J, et al. Mesenchymal stem cells regulate blood-brain barrier integrity through TIMP3 release after traumatic brain injury. Sci Transl Med 2012;4:161ra150.
  2. Pati S, Khakoo AY, Zhao J, et al. Human mesenchymal stem cells inhibit vascular permeability by modulating vascular endothelial cadherin/beta-catenin signaling. Stem Cells Dev 2011;20:89-101.
  3. Gibb SL, Zhao Y, Potter D, et al. TIMP3 Attenuates the Loss of Neural Stem Cells, Mature Neurons and Neurocognitive Dysfunction in Traumatic Brain Injury. STEM CELLS 2015;33:3530-3544.
  4. Park KK, Liu K, Hu Y, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 2008;322:963-966.
  5. Saatman KE, Duhaime AC, Bullock R, et al. Classification of traumatic brain injury for targeted therapies. J Neurotrauma 2008;25:719-738.