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Kobeissy FH, editor. Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Boca Raton (FL): CRC Press/Taylor & Francis; 2015.

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Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects.

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Chapter 42Stem Cell Therapy in Brain Trauma

Implications for Repair and Regeneration of Injured Brain in Experimental TBI Models

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42.1. INTRODUCTION

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.

42.2. POTENTIAL OF ENDOGENOUS NSCs FOR BRAIN REPAIR

42.2.1. Extent of Endogenous Neurogenesis in the Normal Brain

The mature mammalian brain is traditionally considered an organ without regenerative capacity. Recently, this statement was revised after the discovery of multipotent NSCs that are capable of generating neurons and glial cells residing in the mature mammalian brain. The region of neurogenesis in the mature brain is primarily confined to the subventricular zone (SVZ) surrounding the lateral ventricle and the dentate gyrus (DG) of the hippocampus (Altman and Das, 1965; Lois and Alvarez-Buylla, 1993). The majority of the SVZ progeny are neuroblasts that undergo chain migration along the rostral migratory stream to the olfactory bulb, where they differentiate into olfactory interneurons (Doetsch and Alvarez-Buylla, 1996). Another subpopulation of these cells migrate into cortical regions for reasons yet to be identified, but evidence suggests they may be involved in repair or cell renewal mechanisms (Parent, 2002). Likewise, the newly generated cells of the DG migrate laterally into the granule cell layer and exhibit properties of fully integrated mature dentate granule neurons (Kempermann and Gage, 2000; van Praag et al., 2002). Most importantly, the newly generated DG granule neurons form synapses and extend axons into their correct target area, the CA3 region (Hastings and Gould, 1999).

Multiple studies have quantified the degree of cytogenesis occurring in these regions and have clearly shown that large numbers of new cells are regularly produced (Lois and Alvarez-Buylla, 1993; Cameron and McKay, 2001). Specifically, the rat dentate gyrus produces ~9,000 new cells per day, which equates to ~270,000 cells per month (Cameron and McKay, 2001). Considering that the total granule cell population in the rat is 1–2 million cells, this degree of new cell addition is certainly large enough to affect network function. A more recent study has found that in the olfactory bulb almost the entire granule cell population in the deep layer and half of the super layer was replaced by new neurons over a 12-month period (Imayoshi et al., 2008). The same study also reported that in the hippocampus, the adult-generated neurons comprised about 10% of the total number of dentate granule cells and they were equally present along the anteroposterior axis of the DG (Imayoshi et al., 2008). However, studies have also found that in normal adult rodent brains, many newly generated neurons in the DG and nonolfactory-bound SVZ cells have a transient existence of 2 weeks or less (Gould et al., 2001). Although this interval is long enough for supportive glial roles, neuron formation and integration into an existing network takes approximately 10–14 days (Alvarez-Buylla and Nottebohm, 1988; Kirn et al., 1999). It must be noted, however, that a small population of these cells are sustained for months to years (Altman and Das, 1965; Eriksson et al., 1998; Gould et al., 2001), strongly supporting the theory of network integration. Furthermore, this dramatic loss of newly generated cells might be a recapitulation of network pruning seen in early mammalian development. Whether the limited life span represents network pruning or merely distinct cell-specific roles is yet to be understood.

42.2.2. Functions of Adult-Generated Neurons

In the normal hippocampus, the newly generated granular cells in the adult DG can become functional neurons by displaying passive membrane properties, generating action potentials and functional synaptic inputs as seen in mature DG neurons (van Praag et al., 2002). Increasing evidence has also shown that adult hippocampal neurogenesis is involved in learning and memory function (Clelland et al., 2009; Deng et al., 2009). For example, mouse strains with genetically low levels of neurogenesis perform poorly on learning tasks when compared with those with higher level of baseline neurogenesis (Kempermann et al., 1997, 1998). Conversely, physical activity stimulates a robust increase in the generation of new neurons and subsequently enhances spatial learning and long-term potentiation (van Praag et al., 1999a, 1999b). Additionally, diminished hippocampal neurogenesis, as observed after the administration of antimitotic drugs such as methylazoxymethanol acetate, cytosine-β-D-arabinofuranoside, by irradiation or by genetic manipulation, was associated with worse performance on hippocampus-dependent trace eye blink conditioning (Shors et al., 2001), contextual fear conditioning (Saxe et al., 2006; Shors et al., 2002), and long-term spatial memory function tests (Rola et al., 2004; Snyder et al., 2005). Collectively, these studies provide compelling evidence that adult born neurons in the hippocampus play a critical role in many important hippocampal-dependent functions in normal adult brain. Compared with the evident role of hippocampal neurogenesis in hippocampal-dependent functions, the function of SVZ-olfactory neurogenesis is less certain. Thus far, limited studies have found that adult-generated neurons in the olfactory bulb have a critical role in olfactory tissue maintenance and are involved in olfactory discrimination and olfactory perceptual learning functions (Gheusi et al., 2000; Kageyama et al., 2012; Moreno et al., 2009).

The proliferation and maturational fate of cells within the SVZ and DG is modulated by a number of physical and chemical cues. For example, biochemical factors such as serotonin, glucocorticoids, ovarian steroids, and growth factors tightly regulate the proliferative response, suggesting that cell proliferation within these regions have physiologic importance (Banasr et al., 2001; Cameron and Gould, 1994; Kuhn et al., 1997; Tanapat et al., 1999). In addition, certain physical stimuli produce alterations in cell production suggesting a role in network adaptation (Gould et al., 1997; Kempermann et al., 1997b; van Praag et al., 1999b). For example, environments that are cognitively and physically enriched increase cell proliferation and neurogenesis in both the SVZ and DG, whereas stress reduces this type of cellular response (Gould and Tanapat, 1999). Nevertheless, a functional role for these new cells is dependent upon a significant number of cells being generated, and their survival, differentiation, and ultimate integration into existing neuronal circuitry.

42.2.3. Neurogenesis in the Human Brain

Compared with rodent brains, the degree of adult neurogenesis in human brain is less clear. The most well-characterized neurogenic region in the adult human brain is the SVZ lining the lateral ventricle, where a ribbon of SVZ astrocytes have been identified that proliferate in vivo and behave as multipotent progenitor cells in vitro (Sanai et al., 2004). In rodents and primates, neurons born in the SVZ migrate in chains through the rostral migratory stream to replace interneurons of the olfactory bulb currently. In contrast, there is no evidence for chains of migrating neuroblasts in the human SVZ (Sanai et al., 2004). It has been estimated that in normal humans less than 1% of astrocytes within the SVZ ribbon are undergoing cell division and although these endogenous NSCs can be expanded in culture, their response to injury in patients has not been studied. In another neurogenic region in humans, the hippocampal DG neurogenesis in vivo was demonstrated on histological sections obtained in patients who had died of cancer but for which BrdU staining was used for diagnostic purposes (Eriksson et al., 1998). A recent study has found that the generation and migration of new neurons is very much limited to the early childhood (Curtis et al., 2012). Less well-characterized in the human brain are proliferating NPCs in the hippocampus, white matter, and other regions, where cells isolated from the adult human brain are capable of generating both neurons and glia under culture conditions (Kukekov et al., 1999; Murrell et al., 2013; Nunes et al., 2003).

42.2.4. Response of Endogenous NSCs to Brain Injury and the Role of These Cells for Brain Repair

The regenerative capacity of the SVZ and DG is of particular interest with regard to TBI. Because adult-generated neurons from both regions have functional roles, harnessing this endogenous population of stem cells to repopulate the damaged brain is an attractive strategy to repair and regenerate the injured brain. In the injured brain, studies from our laboratory and others have shown that TBI significantly increases cell proliferation in both the SVZ and DG in adult mice and rats in various TBI models including diffuse and focal injury models (Chirumamilla et al., 2002; Rice et al., 2003). We have also found that the juvenile brain has more robust neurogenic response after injury than the adult and aged brain (Sun et al., 2005). Such increased levels of cell proliferation with increased generation of new neurons likely contribute to the better functional recovery in juvenile animals after TBI. Furthermore, we and others have found that injury-induced newly generated granular cells integrate into the existing hippocampal circuitry (Emery et al., 2005; Sun et al., 2007), and this endogenous neurogenesis is associated to the innate cognitive recovery after injury (Sun et al., 2007). In human brain specimens, a recent study has found an increased number of cells expressing NSCs/NPCs markers in the perilesion cortex in the injured brain (Zheng et al., 2013). These studies strongly indicated the inherent attempts of the brain to repair and regenerate after injury through endogenous NSCs.

The degree of endogenous neurogenesis can be enhanced via exogenous means and augmentation of endogenous neural stem cells could be a potential therapy for treating the injured brain. So far, many factors have been shown to enhance neurogenesis particularly in the hippocampus. Studies have found that various types of growth factors and drugs can enhance neurogenesis and improve functional recovery of the injured brain after trauma. For example, studies from our laboratory have shown that intraventricular administration of growth factors basic fibroblast growth factor or epidermal growth factor can significantly enhance TBI-induced cell proliferation in the hippocampus and the SVZ, and drastically improve cognitive functional recovery of the injured adult animals (Sun et al., 2009, 2010). Other studies have found that infusion of S100β or vascular endothelial growth factor can also enhance neurogenesis in the hippocampus and improve the functional recovery of animals after TBI (Kleindienst et al., 2005; Lee and Agoston, 2010; Thau-Zuchman et al., 2010). Several drugs that are currently used in clinical trials for treating TBI or other conditions have shown effects in enhancing neurogenesis and cognitive function in TBI animals including statins (Lu et al., 2007b), erythropoietin (Lu et al., 2005; Xiong et al., 2010), progesterone (Barha et al., 2011), and the antidepressant imipramine (Han et al., 2011). Other strategies that have beneficial effects for TBI such as hypothermia and environment enrichment are also shown enhanced hippocampal neurogenesis in injured animals (Bregy et al., 2012; Kovesdi et al., 2011). Collectively, these studies suggest the therapeutic potential of augmenting the endogenous repair response for treating TBI.

42.3. STEM CELLS AS CELL SOURCE FOR NEURAL TRANSPLANTATION FOR BRAIN REPAIR AND REGENERATION

Because of the limited capacity of the injured brain to repair and replace the damaged neurons, neural transplantation is a prospective therapy for TBI as transplanted cells may differentiate into region-specific cells and integrate into the host tissue to replace the lost cells in the injured brain. Additionally, transplanted cells could provide trophic support to the host tissue to facilitate regeneration. Over the past few decades, researchers have explored a wide array of cell sources for neural transplantation. These cells include embryonic stem cells isolated to fetal or embryonic tissue, mesenchymal stromal cells such as bone marrow stromal cells and umbilical cord cells, adult NSCs, and more recently, induced pluripotent stem cells (iPSCs). The following section will discuss the application of these cell types in the setting of TBI.

42.3.1. Embryonic Stem Cells

Embryonic stem (ES) cells are pluripotent stem cells that have unlimited capacity of self-renewal and can give rise to cells of all three primary germ layers. Because of their high plasticity, ES cells are the ideal cell source for neural transplantation. When transplanted into normal or damaged CNS, human ES cells can differentiate, migrate, and make innervations (Hentze et al., 2007). Thus, ES cells derived from human or mice fetal brains have been tested as a transplantation cell source for TBI treatment in animal studies in different TBI models with different results reported.

NSCs from human ES cells isolated from fetal brain were capable of surviving for an extended period of 6 weeks, migrating to the contralateral cortex, and differentiating into neurons and astrocytes when transplanted into the injured brain after a cortical contusion injury (Wennersten et al., 2004). Gao et al. (2006) have reported that NSCs from human ES cells survived and differentiated to neurons after transplantation into the injured brain when examined at 2 weeks after cell injection, and the injured animals with cell transplantation had improved cognitive functional recovery. In a more recent study, Skardelly et al. (2011) transplanted predifferentiated human fetal ES cells into injured rat brain after a severe controlled cortical injury. They observed a transient increase in angiogenesis and reduced astrogliosis together with improved long-term motor functional improvement, brain injury lesion volume reduction, and increased neuronal survival in the border zone of the lesion. Shear et al. (2004) assessed the long-term survival, migration, differentiation, and functional significance of NSCs derived from mice fetal brain after transplantation into the injured brain up to 1 year posttransplantation. They found that the injured animals receiving transplants showed significant improvement in motor and spatial learning functions, and the transplanted cells migrated widely in the injured brain, with the majority of transplanted cells expressing NG2, an oligodendrocyte progenitor cell marker, but not neuronal markers. Post-TBI neural transplantation of immortalized fetal ES-derived NSCs (C17.2 cells) has also shown improved motor function with the transplanted cells surviving for up to 13 weeks and differentiating into mature neurons and glial cells (Riess et al., 2002; Boockvar et al., 2005). In vitro–modified ES cells either predifferentiated into mature neurons expressing neurotransmitters or with overexpression of growth factors such as glial cell line–derived and brain-derived neurotrophic factor showed beneficial effects when transplanted into the injured animals by promoting motor and cognitive improvement of the injured animals concomitant with better graft survival and neuronal differentiation (Bakshi et al., 2006; Becerra et al., 2007; Ma et al., 2012).

Taken together, these data suggest that post-TBI transplantation using ES-derived cells can restore motor and cognitive functions of the injured animals. However, the beneficial effect of the transplanted cells may be associated with the neural trophic effect of the transplanted cells rather than direct neural replacement as long-term survival and neuronal differentiation is rather limited. Further studies are needed to improve survival and functional neural replacement by modulating the injured host environment. Caution must be exercised when working with multipotent ES cells as undifferentiated ES cells have a potential risk of tumor formation (Riess et al., 2007).

42.3.2. Adult NSCs

Recent findings show that the mature mammalian CNS harbors multipotent stem cells capable of differentiation into a variety of specialized cells throughout life (Gage et al., 1998; Lois and Alvarez-Buylla, 1993). In the adult mammalian CNS, the NSCs/NPCs are primarily confined to the SVZ surrounding the lateral ventricle and the DG of the hippocampus (Altman and Das, 1965; Lois and Alvarez-Buylla, 1993). Aside from these major neurogenic regions, adult neurogenesis in rodents has also been reported in other regions in the CNS including the striatum, the substantia nigra, the cortex, and the spinal cord (Lie et al., 2002; Palmer et al., 1999; Weiss et al., 1996). These adult-derived NSCs express low levels of the major histocompatibility complex antigens (Klassen et al., 2003), display high survival rates, and become region-specific cells when transplanted into normal adult rat brains (Gage et al., 1995; Richardson et al., 2005; Zhang et al., 2003). When transplanted into the injured brain in a rat experimental TBI model, we found that the adult derived NSCs can survive for an extended period in the injured brain. Many cells migrated out of the injection site into the surrounding areas expressing markers for mature astrocytes or oligodendrocytes. Electrophysiological studies showed that the transplanted cells possessed typical mature glial cell properties demonstrating that adult-derived NSCs became region-specific functional cells (Sun et al., 2011) (Figure 42.1).

FIGURE 42.1. Survival and functional differentiation of transplanted adult neural stem and progenitor cells after TBI.

FIGURE 42.1

Survival and functional differentiation of transplanted adult neural stem and progenitor cells after TBI. Cultured adult rat NSCs/NPCs were labeled with BrdU in vitro 3 days before being used for transplantation and subsequently identified with BrdU immunostaining. (more...)

In humans, multipotent stem/progenitors cells have been identified and successfully isolated from various regions of adult human brain including the hippocampus, SVZ, neocortex, and subcortical white matters from neurosurgical resection tissues (Arsenijevic et al., 2001; Brunet et al., 2002, 2003; Kukekov et al., 1999; Nunes et al., 2003; Richardson et al., 2006; Roy et al., 2000; Windrem et al., 2002). These raise the possibility of using such cells as an autologous cell source for transplantation therapy. Indeed, Brunet and colleagues have demonstrated that adult monkey NSCs/NPCs derived from cortical biopsy survived for at least 3 months and displayed a neuronal phenotype after reimplantation into the normal or ibotenic acid excitotoxic-lesioned motor cortex of the donor brains (Brunet et al., 2005). These cells may also restore the anatomy and function of the injured CNS as shown in a study after grafting adult human NSCs/NPCs into the demyelinated rat spinal cord (Akiyama et al., 2001).

To date, very few studies have attempted to examine the behavior of adult-derived human NSCs/NPCs in the injured mature CNS. Olstorn and colleagues recently reported that a small portion (4 ± 1%) of adult human NSCs/NPCs can survive for 16 weeks after transplantation into the posterior periventricular region in normal adult rats or rats with hippocampal CA1 ischemic injury (Olstorn et al., 2007). Although the results of this study are promising, questions remain whether these cells become anatomically and functionally integrated into the injured brain and whether the proportions of surviving cells can be increased by transplanting NSCs/NPC’s at a different developmental stage.

42.3.3. Bone Marrow Stromal Cells

Because of ethical and immunological concerns as well as the risk of tumorigenesis, the translational value of using ES cells for clinic application is limited. Autologous transplantation of NSCs isolated from neurosurgical removal of brain tissue from TBI patients is an attractive strategy; however, so far, the success of long-term cell survival and functional outcomes of these cells in the treatment of experimental TBI is rather limited. Because of these limitations, adult-derived mesenchymal cells, particularly bone marrow stromal cells, (BMSCs) have received much attention.

BMSCs are undifferentiated cells with mixed cell population including stem and progenitor cells. These cells can be easily isolated from the mononuclear fraction of patients’ bone marrow and be expanded in culture without ethical and technical concerns. Another advantage of considering BMSCs for cell transplantation is the low antigenicity because of their low expression of the major histocompatibility complex antigens (class II) (Le and Ringden, 2005). In addition, these cells produce high levels of growth factors, cytokines, and extracellular matrix molecules that could have potential neurotrophic or neuroprotective effect in the injured brain. As a matter of fact, all studies using BMSCs for neural transplantation have demonstrated that the beneficial effects of BMSCs are attributed to their neurotrophic or neuroprotective effect rather than direct cell replacement (Li and Chopp, 2009).

The potential of BMSCs for treating TBI have been extensively assessed in experimental TBI models. Cells were delivered either focally to the injured brain, or systemically through intravenous or intraarterial injections at the acute or subacute phase after TBI and significant reduction of neurological deficits including motor and cognitive deficits were reported. For example, intracranial injection of rat BMSCs into the brain region adjacent to the brain lesion site or intravenous injection of cells at 24 hours after a controlled cortical contusion injury in rats and it was found that the injured animals had improved sensory motor functional (Lu et al., 2001; Mahmood et al., 2001, 2003). When human BMSCs were combined with collagen scaffolds and transplanted into the injury cavity at 4 or 7 days after TBI, animals had significantly improved sensorimotor and spatial learning functions together with reduced brain lesion volume and enhanced focal brain angiogenesis (Lu et al., 2007a; Xiong et al., 2009). The effect of BMSCs in improving sensorimotor function of injured animals was reported even when delivered at 2 months after TBI (Bonilla et al., 2009). Further studies have demonstrated that the beneficial effort of BMSCs in the injured brain is due largely by their production of bioactive factors, which facilitates the endogenous plasticity and remodeling of the host brain thus promoting functional recovery (Li and Chopp, 2009). Although a low number of BMSCs can be found in the injured brain expressing neuronal or glial markers (Mahmood et al., 2001, 2003), no study has demonstrated that BMSCs can become fully differentiated functional neurons in vivo. Taken together, extensive experimental studies have demonstrated the beneficial effects of BMSCs in the injured brain and highlighted the potential use of BMSCs

42.3.4. Other Potential Types of Stem Cells for Cell Replacement Therapy

Apart from the previously mentioned stem cells, researchers have recently explored several other types of stem or stem-like cells for TBI application. Published data have reported that the use of human amnion–derived multipotent progenitor cells can significantly attenuate axonal degeneration and improve neurological function and brain tissue morphology of the injured rats (Chen et al., 2009; Yan et al., 2013). Intravenous administration of human adipose–derived stem cells or the derived culture medium into a controlled cortical impact rat model significantly improved motor and cognitive functions and reduced focal tissue damage and hippocampal cell loss (Tajiri et al., 2014).

Human umbilical cord blood is an abundant source of multiple stem cells, including hematopoietic stem cells, mesenchymal stem cells, unrestricted somatic stem cells, and embryonic-like stem cells. These cells can be easily harvested without ethical controversy and could be an attractive source of stem cells for brain repair. These studies have shown that these cells can survive in injury sites and promote survival of local host neurons in ischemic and spinal cord injury animal models (Sun and Ma, 2013). In a recent study, Wang et al. have conducted a small-scale clinical trial using these cells for treating TBI patients. The authors reported that the patients treated with umbilical cord stem cells had improved neurological function and self-care compared with control group (Wang et al., 2013).

Recent development of somatic cell reprogramming that generates iPSCs provides prospects for novel neural replacement strategies. Human iPSCs possess the dual properties of unlimited self-renewal and the pluripotent potential to differentiate into multilineage cells without ethical concerns. More importantly, patient-specific iPSCs can serve as an autologous cell source for transplantation without encountering graft rejection. These unique properties of iPSCs have raised the widespread hope that many neurological diseases including TBI might be cured or treated. Thus far rapid progress has been made in the field of reprogramming; however, the optimal source of somatic cells used for applications in neurological disorders has not been identified yet.

42.4. CONCLUSION AND PERSPECTIVES

The existence of multipotent stem cells in the mammalian brain and other organs has raised high enthusiasm for using these cells to treat the injured brain. Extensive studies have shown the potential brain repair through endogenous NSCs or through cell replacement strategies using varying types of stem cells. However, to successfully repair and regenerate the injured brain with stem cells, many challenges must be overcome. One major challenge is generation of sufficient functional neurons capable of integrating into existing neural circuitry in the injured brain. Another major challenge, which is particularly important for stem cell transplantation, is the focal microenvironment of the site of injury. After TBI, primary brain damage together with secondary tissue loss induced by ischemia, excitotoxicity, oxidative stress, and inflammation create a hostile environment preventing the survival and integration of the transplanted cells. So far, ample studies have supported the notion that the in vivo fate of transplanted cells is regulated by the intrinsic properties of grafted cells and the local environmental cues in the host. These challenges must be overcome in experimental TBI studies before moving forward with stem cell therapies for treating the injured brain clinically.

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