Endogenous Stem and Progenitor Cell Responses of the Subventricular Zone and Cortex Following Traumatic Brain Injury

Despite years of research, the current neurotrauma field is unable to offer any treatment to address the persistent loss of function that can often occur after a traumatic brain injury (TBI). Although physical therapy and rehabilitation may improve quality of life for some NI patients, the majority continue to require specialized care, and seldom resume fully productive lives. There is an urgent need for novel research approaches into potential therapies that can promote functional recovery after TBI, and stem cells may offer some potential in this regard. There is currently little information on the contribution that neural stem cells might make to the significant spontaneous functional recovery, which occurs in the weeks following injury in rodent models of TBI, and months to years following human injury. Fundamental questions regarding the effect of injury on basic stem cell biology of the neurogenic subventricular zone (SVZ) and in the cortex require resolution before we can begin to address much bigger questions about the contribution that these cells might make to functional recovery, and whether or not interventions could enhance this effect in vivo. The work in dissertation has therefore been aimed toward gaining a better understanding of the cellular responses of the SVZ as well as the injured cortex and the interaction between the two regions.;In the first study, the TBI-induced proliferative response of the SVZ was determined to occur as a result of increased division of a population of transit-amplifying cells expressing Mash1. Surprisingly, the SVZ GFAP+ cell population which is enriched for stem cells remains relatively quiescent after injury, and although they give rise to the Mash1+ cells that are stimulated to divide, they themselves do not divide more after injury. EGFR+ cells, which are also normally largely transit-amplifying cells, are affected differently than their Mash1+ counterparts, as they become less proliferative after injury. The data suggests that a non-proliferative increase in GFAP+ cells occurs, as these EGFR+ cells are likely halted, or reverted back in lineage to an activated stem cell state as opposed to progressing to a transit-amplifying state.;In the second and third studies of this dissertation, a dual-thymidine analog-labeling paradigm was implemented in order to identify subpopulations of label-retaining cells, based on the retention of IdU label. The cellular response within the injured cortex was shown to be multifaceted, involving a local endogenous cortical reaction, DCX-dependent cell migration from the SVZ, as well as a DCX-independent source of cells from the SVZ and/or other brain regions. Surprisingly, however, the early proliferative response observed within the injured cortex does not depend on the contribution of GFAP-derived stem and progenitor cells from the SVZ, which leads to further questions regarding the contribution of the SVZ response to potential repair mechanisms in the injured cortex. Future work on the brain environmental cues is required to understand how cell migration, survival, and integration after injury can be maximized, with the ultimate goal of developing useful therapeutic interventions to ameliorate the symptoms of TBI.