INDUCED PLURIPOTENT STEM CELL TROPISM AND PARACRINE EFFECTS IN TWO MOUSE MODELS OF GREY AND WHITE MATTER TRAUMATIC BRAIN INJURY

Exposure to blast, bullets and shrapnel, vehicle crashes and falls significantly elevate the risk of traumatic brain injury (TBI) in military personnel. TBI can lead to a spectrum of functional deficits that range from impairments in motor and sensory behaviors to loss of memory, poor executive functioning, as well as psychological problems such as post-traumatic stress disorder (PTSD) and social dislocation. Conventional approaches to clinical TBI research have been reductionist focusing on single factors for therapeutic targeting. The heterogeneity of TBI causes, pathophysiology and outcomes has meant that this approach has been unsuccessful. Stem cell-based therapies offer the prospect of polytherapy from a single intervention to modify tissue integrity and host immune responses. However, a detailed understanding of how stem cells function within the damaged brain and how these cells contribute to tissue regeneration will be necessary to translate this approach to the clinic. Furthermore, determining the range of efficacy of any stem cell therapy will require testing in multiple pre-clinical injury models to reflect the heterogeneity of TBI causes, pathophysiology and outcomes. The goal of this pre-clinical study is to gain in-depth functional knowledge of human stem cell-derived neurons and astrocytes grafted into two distinct models of TBI in mice, a grey matter contusion model and a closed-head model of white matter axonal injury. The effect of stem cell transplantation on the damaged host environment will be measured using a series of TBI pathological markers. We believe matching the types of stem cell grafts to distinct causes and pathologies of TBI will be critical in establishing effective regenerative medicine strategies to limit damage and restore function lost to TBI. This proposal will make a significant advancement toward that effort and will generate important pre-clinical data on the use of regenerative medicine strategies to treat TBI.