Background: The attainment of extensive neurological function recovery remains the key challenge for the treatment of traumatic brain injury (TBI). Transplantation of bone marrow-derived mesenchymal stem cells (BMSCs) has been shown to improve neurological function recovery after TBI. However, the survival of BMSCs after transplantation in early-stage TBI is limited, and much is unknown about the mechanisms mediating this neurological function recovery. Secretion of neurotrophic factors, including neurotrophin 3 (NT3), is one of the critical factors mediating BMSC neurological function recovery. Gene mutation of NT3 (NT3 P75-2) has been shown to enhance the biological function of NT3 via the reduction of the activation of the P75 signal pathway. Thus, we investigated whether NT3 P75-2 gene-modified BMSCs could enhance the survival of BMSCs and further improve neurological function recovery after TBI. Methods: The ability of NT3 P75-2 induction to improve cell growth rate of NSC-34 and PC12 cells in vitro was first determined. BMSCs were then infected with three different lentiviruses (green fluorescent protein (GFP), GFP-NT3, or GFP-NT3 P75-2), which stably express GFP, GFP-NT3, or GFP-NT3 P75-2. At 24 h post-TBI induction in mice, GFPlabeled BMSCs were locally transplanted into the lesion site. Immunofluorescence and histopathology were performed at 1, 3, and/or 7 days after transplantation to evaluate the survival of BMSCs as well as the lesion volume. A modified neurological severity scoring system and the rotarod test were chosen to evaluate the functional recovery of the mice. Cell growth rate, glial activation, and signaling pathway analyses were performed to determine the potential mechanisms of NT3 P75-2 in functional recovery after TBI. Results: Overall, NT3 P75-2 improved cell growth rate of NSC-34 and PC12 cells in vitro. In addition, NT3 P75-2 significantly improved the survival of transplanted BMSCs and neurological function recovery after TBI. Overexpression of NT3 P75-2 led to a significant reduction in the activation of glial cells, brain water content, and brain lesion volume after TBI. This was associated with a reduced activation of the p75 neurotrophin receptor (P75NTR) and the c-Jun N-terminal kinase (JNK) signal pathway due to the low affinity of NT3 P75-2 for the receptor. Conclusions: Taken together, our results demonstrate that administration of NT3 P75-2 gene-modified BMSCs dramatically improves neurological function recovery after TBI by increasing the survival of BMSCs and ameliorating the inflammatory environment, providing a new promising treatment strategy for TBI.

Stroke is an acute cerebrovascular disorder caused by sudden decrease or interruption of blood flow in brain arteries. Deficiency of timely and effective reperfusion of ischemic brain tissue can lead to irreversible brain injury and neurological dysfunction. Currently, recombinant tissue plasminogen activator (rt-PA) is the only appropriate thrombolytic agent which is approved by FDA for patients with acute ischemic stoke. However, due to the limitation of very narrow therapeutic time window and severe intracranial hemorrhagic complication, the outcome of stroke treatment mediated by rt-PA still remains unsatisfactory. Therefore, it is urgent to find new alternative drugs or develop novel drug delivery system to achieve better outcomes. In recent years, with the rapid development of nanotechonology, nanomaterials as a drug delivery system can provide new strategies and methods to carry t-PA specifically to the occlusion site and provide advanced treatment for stroke. In this review, we briefly introduced the physiopathologic mechanisms of thrombolysis and focused on the comparison of the t-PA mediated thrombolysis and t-PA conjugated nanomaterial mediated thrombolysis.

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