Traumatic brain injury is a recognized risk factor for later development of neurodegenerative disease. Brain injuries poses a significant financial burden to society as well as a physical and psychiatric burden to victims and caregivers. The severity of traumatic brain injury (TBI) ranges from mild to severe, with mild traumatic brain injury/concussion being three times more common than moderate and severe brain injury combined. Current acute treatment of TBI is limited to controlling intracranial pressure and there is no therapy to reverse the primary or secondary injuries associated with any severity of TBI. The use of Neural Stem Cells (NSCs) in treatment of TBI has gain enormous interest over the last decade. Partly because of their good safety record in the current clinical trials for stroke or cancer, their ability to migrate across the blood brain barrier, and also by their ability to circumvent one of the major hurdle in treating TBI, which is a selective and targeted delivery to the injured tissues. Other advantages such of their immunosuppressive properties and their capability of secreting growth factors that could halt the progression of the secondary insult make them particularly appealing as a regenerative therapy post TBI. The goal of this application is to use intranasal delivery of a known doses of a well-characterized, immortalized human allogeneic NSC line (LM-NSC008) to repair the brain tissues damaged after mild TBI. Intranasal administration of NSCs, when compared with intracranial administration, appears to be the least invasive and most feasible and cost-effective option for delivering cells to the brain for repeated treatment rounds with a focus on patients experiencing long term symptoms (15% of all mTBI). We will determine the doses and therapeutic efficacy of five intranasal injection of LM-NSC008 cells in our experimental mouse model of mild TBI. Ex vivo 2-photon confocal microscopy of brain sections and CLARITY will be used to reconstruct brains three-dimensionally and to quantify the TBI sites coverage by NSCs at 17 days post last injury. This proposal will also evaluate NSCs survival, engraftment, and associated functional outcome at 2 months post repetitive mild TBI. We hypothesize that the ongoing inflammation observed in the white matter of the injured animals of our experimental model of mTBI could be alleviated by multiple intranasal injections of NSCs and improve functional recovery. Because LM-NSC008 cells has been shown to migrate through the sub cortical white matter tracts, we anticipate to see, a decrease in reactive gliois in the major white matter tracts concurrent with a decrease in proinflammatory cytokines that correlates with an amelioration of injury-induced cognitive deficits. Successful translation of this approach would be a major advance over current methods of stem cell delivery to the brain and could be widely applied to new therapeutic NSC-based therapies for neurodegenerative diseases.
A major obstacle to successfully treat Traumatic Brain Injury (TBI) is to have a drug or cells that that cross the blood-brain barrier and selectively target the injured brain tissue. Neural stem cells (NSCs) offer a potential solution to treat TBI by passing the blood-brain barrier and delivering undifferentiated cells that have the potential to differentiate into multiple cell lines, and provide restorative resources to surviving cells. The proposed studies use our model of mild TBI to determine the biodistribution and therapeutic efficacy of a well characterized immortalized human allogeneic NSC line (LM-NSC008) to accelerate clinical translation of NSC-based therapies to patients with TBI and other neurodegenerative diseases.
