Traumatic Brain Injury and Stem Cell: Pathophysiology and Update on Recent Treatment Modalities

Abstract

Traumatic brain injury (TBI) is a complex condition that presents with a wide spectrum of clinical symptoms caused by an initial insult to the brain through an external mechanical force to the skull. In the United States alone, TBI accounts for more than 50,000 deaths per year and is one of the leading causes of mortality among young adults in the developed world. Pathophysiology of TBI is complex and consists of acute and delayed injury. In the acute phase, brain tissue destroyed upon impact includes neurons, glia, and endothelial cells, the latter of which makes up the blood-brain barrier. In the delayed phase, "toxins" released from damaged cells set off cascades in neighboring cells eventually leading to exacerbation of primary injury. As researches further explore pathophysiology and molecular mechanisms underlying this debilitating condition, numerous potential therapeutic strategies, especially those involving stem cells, are emerging to improve recovery and possibly reverse damage. In addition to elucidating the most recent advances in the understanding of TBI pathophysiology, this review explores two primary pathways currently under investigation and are thought to yield the most viable therapeutic approach for treatment of TBI: manipulation of endogenous neural cell response and administration of exogenous stem cell therapy.

Figure 1

After TBI, exogenous stem stimulate proliferation of endogenous neural stem cells (a). After TBI, there is induction of neurogenesis (b) post-TBI infusion of VEGF. After TBI and rupture of the blood-brain barrier, macrophages will stimulate an initial phase of phagocytic, proteolytic, and proinflammatory functions, while the second phase is characterized by anti-inflammatory functions, which includes regeneration, growth, angiogenesis, and matrix deposition. Microglia initiate inflammatory events. This figure also demonstrates neutrophil invasion and their impact on pathological processes of brain trauma, which includes alteration of vascular permeability and contribution to oxidative damage via secretion of lysosomal enzymes, and changes in cerebral blood flow. In addition, neutrophils act by releasing inflammatory cytokines such as IL-6, IL-1, and tumor necrosis factor alpha (TNF-α) (c). Microglia, monocytes, macrophages, and neutrophils invade areas exhibiting blood-brain barrier damage, and there is extensive upregulation of neutrophil adhesion factors including integrin receptors. Gerry Shaw, microglia and neurons, 25 July 2005, by Creative Commons; hematologist, segmented neutrophils, 31 August 2009, Creative Commons; microphages by Patho via Wikimedia Commons; microglia by Frontier in Cellular Neuroscience, 30 January 2013, Creative Commons.