Human neural stem cells (hNSCs) possess significant therapeutic potential for the treatment of traumatic brain injury (TBI), a leading cause of global death and disability. Recent pre-clinical studies have shown that hNSCs reduce tissue damage and promote functional recovery through neuroprotective and regenerative signaling and cell replacement. Yet the overall efficacy of hNSCs for TBI indications remains unclear. Therefore, this systematic review aims to evaluate hNSC interventions compared with controls in pre-clinical TBI models. Through this process, variations in hNSC administration protocols were consolidated, and key knowledge gaps were identified. Meta-analysis was applied to primary outcomes of lesion volume, Morris Water Maze (MWM) performance, modified Neurological Severity Scores (mNSS), and the rotarod task. Narrative review of secondary outcomes included hNSC survival and differentiation, endogenous neuron survival, axonal injury, and inflammation. Overall, hNSC intervention reduced lesion volume, enhanced MWM performance, and led to trending decreases in acute and chronic neurological deficits at acute and chronic time points. These results suggest hNSCs demonstrate clear efficacy in pre-clinical TBI models. However, further studies are needed to address key questions regarding optimal hNSC administration (e.g., dosing, treatment window) and underlying mechanisms of action prior to progressing to human clinical trials.

Traumatic brain injury (TBI) is a leading cause of death and disability in pediatric patients and often results in delayed neural development and altered connectivity, leading to lifelong learning, memory, behavior, and motor function deficits. Induced pluripotent stem cell-derived neural stem cells (iNSCs) may serve as a novel multimodal therapeutic as iNSCs possess neuroprotective, regenerative, and cell-replacement capabilities post-TBI. In this study, we evaluated the effects of iNSC treatment on cellular, tissue, and functional recovery in a translational controlled cortical impact TBI piglet model. Five days post-craniectomy (n = 6) or TBI (n = 18), iNSCs (n = 7) or PBS (n = 11) were injected into perilesional brain tissue. Modified Rankin Scale (mRS) neurological evaluation, magnetic resonance imaging, and immunohistochemistry were performed over the 12-week study period. At 12-weeks post-transplantation, iNSCs showed long-term engraftment and differentiation into neurons, astrocytes, and oligodendrocytes. iNSC treatment enhanced endogenous neuroprotective and regenerative activities indicated by decreasing intracerebral immune responses, preserving endogenous neurons, and increasing neuroblast formation. These cellular changes corresponded with decreased hemispheric atrophy, midline shift, and lesion volume as well as the preservation of cerebral blood flow. iNSC treatment increased piglet survival and decreased mRS scores. The results of this study in a predictive pediatric large-animal pig model demonstrate that iNSC treatment is a robust multimodal therapeutic that has significant promise in potentially treating human pediatric TBI patients.

Cortical traumatic brain injury (TBI) is a major cause of cognitive impairment accompanied by motor and behavioral deficits, and there is no effective treatment strategy in the clinic. Cell transplantation is a promising therapeutic strategy, and it is necessary to verify the survival and differentiation of cells after transplantation in large animal models like rhesus monkeys. In this study, we transplanted neural stem cells (NSCs) and simultaneously injected basic fibroblast growth factor/epidermal growth factor (bFGF/EGF) into the cortex (visual and sensory cortices) of rhesus monkeys with superficial TBI. The results showed that the transplanted NSCs did not enter the cerebrospinal fluid (CSF) and were confined to the transplantation site for at least one year. The transplanted NSCs differentiated into mature neurons that formed synaptic connections with host neurons, but glial scar formation between the graft and the host tissue did not occur. This study is the first to explore the repairing effect of transplanting NSCs into the superficial cerebral cortex of rhesus monkeys after TBI, and the results show the ability of NSCs to survive long-term and differentiate into neurons, demonstrating the potential of NSC transplantation for cortical TBI.

Normoxia is defined as an oxygen concentration of 20.9%, as in room air, whereas hypoxia refers to any oxygen concentration less than this. Any physiological oxygen deficiency or tissue oxygen deficiency relative to demand is called hypoxia. Neural stem cells (NSCs) are multipotent stem cells that can differentiate into multiple cell lines such as neurons, oligodendrocytes, and astrocytes. Under hypoxic conditions, the apoptosis rate of NSCs increases remarkably in vitro or in vivo. However, some hypoxia promotes the proliferation and differentiation of NSCs. The difference is related to the oxygen concentration, the duration of hypoxia, the hypoxia tolerance threshold of the NSCs, and the tissue source of the NSCs. The main mechanism of hypoxia-induced proliferation and differentiation involves an increase in cyclin and erythropoietin concentrations, and hypoxia-inducible factors play a key role. Multiple molecular pathways are activated during hypoxia, including Notch, Wnt/β-catenin, PI3K/Akt, and altered microRNA expression. In addition, we review the protective effect of exogenous NSCs transplantation on ischemic or anoxic organs, the therapeutic potential of hypoxic preconditioning on exogenous NSCs and clinical application of NSCs.

Neurological disorders are big public health challenges that are afflicting hundreds of millions of people around the world. Although many conventional pharmacological therapies have been tested in patients, their therapeutic efficacies to alleviate their symptoms and slow down the course of the diseases are usually limited. Cell therapy has attracted the interest of many researchers in the last several decades and has brought new hope for treating neurological disorders. Moreover, numerous studies have shown promising results. However, none of the studies has led to a promising therapy for patients with neurological disorders, despite the ongoing and completed clinical trials. There are many factors that may affect the outcome of cell therapy for neurological disorders due to the complexity of the nervous system, especially cell types for transplantation and the specific disease for treatment. This paper provides a review of the various cell types from humans that may be clinically used for neurological disorders, based on their characteristics and current progress in related studies.

Brain diseases, including brain tumors, neurodegenerative disorders, cerebrovascular diseases, and traumatic brain injuries, are among the major disorders influencing human health, currently with no effective therapy. Due to the low regeneration capacity of neurons, insufficient secretion of neurotrophic factors, and the aggravation of ischemia and hypoxia after nerve injury, irreversible loss of functional neurons and nerve tissue damage occurs. This damage is difficult to repair and regenerate the central nervous system after injury. Neural stem cells (NSCs) are pluripotent stem cells that only exist in the central nervous system. They have good self-renewal potential and ability to differentiate into neurons, astrocytes, and oligodendrocytes and improve the cellular microenvironment. NSC transplantation approaches have been made for various neurodegenerative disorders based on their regenerative potential. This review summarizes and discusses the characteristics of NSCs, and the advantages and effects of NSCs in the treatment of brain diseases and limitations of NSC transplantation that need to be addressed for the treatment of brain diseases in the future.

Traumatic brain injury (TBI) is a substantial cause of disability and death worldwide. Primary head trauma triggers chronic secondary injury mechanisms in the brain that are a focus of therapeutic efforts to treat TBI. Currently, there is no successful clinical strategy to repair brain injury. Cell transplantation therapies have demonstrated promise in attenuating secondary injury mechanisms of neuronal death and dysfunction in animal models of brain injury. In this study, we used a unilateral cortical contusion injury (CCI) model of sensorimotor brain injury to examine the effects of human induced pluripotent stem cell (hiPSC) transplantation on pathology in male and female adult mice. We determined transplanted hiPSC-derived neural stem cells (NSCs) and neuroblasts but not astrocytes best tolerate the injured host environment. Surviving NSC and neuroblast cells were clustered at the site of injection within the deep layers of the cortex and underlying corpus callosum. Cell grafts extended neuritic processes that crossed the midline into the contralateral corpus callosum or continued laterally within the external capsule to enter the ipsilateral entorhinal cortex. To determine the effect of transplantation on neuropathology, we performed sensorimotor behavior testing and stereological estimation of host neurons, astrocytes, and microglia within the contused cortex. These measures did not reveal a consistent effect of transplantation on recovery post-injury. Rather the positive and negative effects of cell transplantation were dependent on the host sex, highlighting the importance of developing patient-specific approaches to treat TBI. Our study underscores the complex interactions of sex, neuroimmune responses and cell therapy in a common experimental model of TBI.

Human neural stem cells (hNSCs) transplantation in several brain injury models has established their therapeutic potential. However, the feasibility of hNSCs transplantation is still not clear for acute subdural hematoma (ASDH) brain injury that needs external decompression. Thus, the aim of this pilot study was to test feasibility using a rat ASDH decompression model with two clinically relevant transplantation methods. Two different methods, in situ stereotactic injection and hNSC-embedded matrix seating on the brain surface, were attempted. Athymic rats were randomized to uninjured or ASDH groups (F344/NJcl-rnu/rnu, n = 7-10/group). Animals in injury group were subjected to ASDH, and received decompressive craniectomy and 1-week after decompression surgery were transplanted with green fluorescent protein (GFP)-transduced hNSCs using one of two approaches. Histopathological examinations at 4 and 8 weeks showed that the GFP-positive hNSCs survived in injured brain tissue, extended neurite-like projections resembling neural dendrites. The in situ transplantation group had greater engraftment of hNSCs than matrix embedding approach. Immunohistochemistry with doublecortin, NeuN, and GFAP at 8 weeks after transplantation showed that transplanted hNSCs remained as immature neurons and did not differentiate toward to glial cell lines. Motor function was assessed with rotarod, compared to control group (n = 10). The latency to fall from the rotarod in hNSC in situ transplanted rats was significantly higher than in control rats (median, 113 s in hNSC vs. 69 s in control, P = 0.02). This study first demonstrates the robust engraftment of in situ transplanted hNSCs in a clinically-relevant ASDH decompression rat model. Further preclinical studies with longer study duration are warranted to verify the effectiveness of hNSC transplantation in amelioration of TBI induced deficits.

The study of neurogenesis and neural progenitor cells (NPCs) is important across the biomedical spectrum, from learning about normal brain development and studying disease to engineering new strategies in regenerative medicine. In adult mammals, NPCs proliferate in two main areas of the brain, the subventricular zone (SVZ) and the subgranular zone, and continue to migrate even after neurogenesis has ceased within the rest of the brain. In healthy animals, NPCs migrate along the rostral migratory stream (RMS) from the SVZ to the olfactory bulb, and in diseased animals, NPCs migrate toward lesions such as stroke and tumors. Here we review how MRI-based cell tracking using iron oxide particles can be used to monitor and quantify NPC migration in the intact rodent brain, in a serial and relatively non-invasive fashion. NPCs can either be labeled directly in situ by injecting particles into the lateral ventricle or RMS, where NPCs can take up particles, or cells can be harvested and labeled in vitro, then injected into the brain. For in situ labeling experiments, the particle type, injection site, and image analysis methods have been optimized and cell migration toward stroke and multiple sclerosis lesions has been investigated. Delivery of labeled exogenous NPCs has allowed imaging of cell migration toward more sites of neuropathology, which may enable new diagnostic and therapeutic opportunities for as-of-yet untreatable neurological diseases.

Traumatic brain injury (TBI) has been recognized as one of the major public health issues that leads to devastating neurological disability. As a consequence of primary and secondary injury phases, neuronal loss following brain trauma leads to pathophysiological alterations on the molecular and cellular levels that severely impact the neuropsycho-behavioral and motor outcomes. Thus, to mitigate the neuropathological sequelae post-TBI such as cerebral edema, inflammation and neural degeneration, several neurotherapeutic options have been investigated including drug intervention, stem cell use and combinational therapies. These treatments aim to ameliorate cellular degeneration, motor decline, cognitive and behavioral deficits. Recently, the use of neural stem cells (NSCs) coupled with selective drug therapy has emerged as an alternative treatment option for neural regeneration and behavioral rehabilitation post-neural injury. Given their neuroprotective abilities, NSC-based neurotherapy has been widely investigated and well-reported in numerous disease models, notably in trauma studies. In this review, we will elaborate on current updates in cell replacement therapy in the area of neurotrauma. In addition, we will discuss novel combination drug therapy treatments that have been investigated in conjunction with stem cells to overcome the limitations associated with stem cell transplantation. Understanding the regenerative capacities of stem cell and drug combination therapy will help improve functional recovery and brain repair post-TBI. This article is part of the Special Issue entitled "Novel Treatments for Traumatic Brain Injury".