Stem Cell Therapy in Brain Trauma: Implications for Repair and Regeneration of Injured Brain in Experimental TBI Models

Abstract

Traumatic brain injury (TBI) is a major health problem worldwide. Currently, there is no effective treatment to improve neural structural repair and functional recovery of patients in clinic. Recent studies suggest that adult neural stem/progenitor cells residing in the neurogenic regions in the adult mammalian brain may play regenerative and reparative roles in response to CNS injuries or diseases. Alternatively, cell transplantation is a potential strategy to repair and regenerate the injured brain. This chapter will discuss the potential of neural stem cells to repair the injured brain with emphasize on modulating endogenous adult neurogenesis to promote regeneration following TBI. The potential of neural stem cells for neural transplantation to repair the injured brain will also been discussed.Approximately 350,000 individuals in the United States are affected annually by severe and moderate TBI that may result in long-term disability. This rate of injury has produced more than 3 million disabled citizens in the United States alone. Despite generally improving rates of survival after TBI, approximately 80,000 individuals in the United States annually sustain TBIs that result in significant long-term disability. These impairments involve both memory and behavior and can result in a total vegetative state. Most of these 3 million survivors depend upon others for daily care. Many clinical and animal model studies have now shown that severe and even moderate TBI is characterized by both neuronal and white matter loss with resultant brain atrophy and functional neurological impairment. Injury may be in the form of focal damage because it typically occurs after acute subdural hematoma, or it may be diffuse with widespread delayed neuronal loss as it typically occurs after diffuse axonal injury. To date, there is no effective treatment for TBI. Current therapies are primarily focused on reducing the extent of secondary insult rather than repairing the damage from the primary injury. After TBI, the hippocampus is particularly vulnerable to the secondary insults. Hippocampal injury associated to learning and memory deficits are the hallmarks of brain trauma and are the most enduring and debilitating of TBI deficits because they prevent reintegration of patients into a normal lifestyle by impairing employment and social interactions. Spontaneous cognitive improvement is not uncommon but is greatly limited and not normally seen past the second year postinjury (Schmidt et al., 1999). This natural recovery, however, does suggest that innate mechanisms for repair and regeneration are present within the brain.Recent findings reveal that multipotent neural stem cells/progenitor cells (NSCs/NPCs) persist in selected regions of the brain throughout the life span of an animal, rendering the brain capable of generating new neurons and glia (Gage et al., 1998; Lois and Alvarez-Buylla, 1993). Furthermore, increasing evidence indicates that these endogenous NSCs/NPCs may play regenerative and reparative roles in response to central nervous system (CNS) injuries or diseases. In support of this notion, heightened levels of cell proliferation and neurogenesis have been observed in response to brain trauma or insults suggesting that the brain has the inherent potential to restore populations of damaged or destroyed neurons. This raises the possibility of developing therapeutic strategies aiming at harnessing this neurogenic capacity to repopulate and repair the damaged brain. Recent experimental successes in cell replacement in models of Parkinson disease and other neurodegenerative diseases have inspired TBI researchers to investigate this approach for treating the injured brain. The therapeutic prospects of cell transplantation are based on the potential for transplanted cells to differentiate into region-specific cells and integrate into the host tissue to replace lost cells in the injured brain; alternatively, transplanted cells could provide neurotransmitters or trophic support to the host tissue to facilitate survival or regeneration.These two approaches, through modulating endogenous NSCs or using exogenous stem cells, are gaining increasing attention in the field of neural regeneration. This chapter will review recent understanding and progress in experimental TBI therapeutic development with endogenous neurogenesis and neural transplantation.