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Traumatic Brain Injury (TBI) gives rise to a progressive disease state that results in many adverse and long-term neurological consequences, including deficits in learning and memory, development of major depressive disorder, and increased likelihood of developing neurodegenerative diseases, as well as decreased life expectancy. Mesenchymal stem cells (MSC) have emerged as a promising cytotherapy for TBI and have been previously shown to improve numerous cellular and behavioral outcomes after brain injury including reduction of secondary apoptosis, restriction of immune cell infiltration, and improvements in cognitive deficits such as spatial learning and memory. A number of molecules secreted by MSC have been implicated in their therapeutic mechanism of action. However, no studies have been conducted to examine the how the MSC secretome collectively regulates the injury microenvironment to support the survival of intact brain tissue that would otherwise be subject to secondary injury. The present study, uses high throughput RNA sequencing (RNAseq) of cortical tissue from the TBI penumbra to assess the molecular effects of both TBI and subsequent treatment with intravenously delivered human mesenchymal stem cells (hMSC). TBI was found to disrupt expression of approximately one quarter of the rat protein-encoding genome. Remarkably, hMSC treatment was found to normalize 49% of all transcripts regulated by TBI. This study also investigates the therapeutic efficacy of hMSC against negative behavioral outcomes commonly associated with TBI, including depression, which is the most common long-term side effect of TBI in humans. We show for the first time that a stem cell-based therapy is capable of preventing trauma-induced depression. Using novel precision X-ray methods to selectively eliminate endogenous neural stem cells, this study further probes the cellular mechanisms that underlie hMSC efficacy to reveal that some, but not all, therapeutic benefits conferred by hMSC treatment are dependent on active proliferation of endogenous neural progenitor cells in the subventricular zone.