Several studies have implicated the aquaporins (aqp) 1, 4, and 9 in the pathogenesis of malignant brain tumours, suggesting that they contribute to motility, invasiveness, and oedema formation and facilitate metabolism in tumour cells under hypoxic conditions. We have studied the expression of aqp1, 4, and 9 in biopsies from glioblastomas, isolated tumour stem cells grown in a tumoursphere assay and analyzed the progenitor and differentiated cells from these cultures. We have compared these to the situation in normal rat brain, its stem cells, and differentiated cells derived thereof. In short, qPCR in tumour tissue showed presence of aqp1, 4, and 9. In the tumour progenitor population, aqp9 was markedly more highly expressed, whilst in tumour-derived differentiated cells, aqp4 was downregulated. However, immunostaining did not reveal increased protein expression of aqp9 in the tumourspheres containing progenitor cells; in contrast, its expression (both mRNA and protein) was high in differentiated cultures. We, therefore, propose that aquaporin 9 may have a central role in the tumorigenesis of glioblastoma.

Experimental diabetes in rodents rapidly affects the neurogenic niches of the adult brain. Moreover, behavioral disorders suggest that a similar dysfunction of the neurogenic niches most likely affects diabetic and prediabetic patients. Here, we review our present knowledge about adult neural stem cells, the methods used for their study in diabetic models, and the effects of experimental diabetes. Variations in diet and even a short hyperglycemia profoundly change the structure and the proliferative dynamics of the neurogenic niches. Moreover, alterations of diabetic neurogenic niches appear to be associated with diabetic cognitive disorders. Available evidence supports the hypothesis that, in the adult, early changes of the neurogenic niches might enhance development of the diabetic disease.

Neural stem cells are the origins of neurons and glia and generate all the differentiated neural cells of the mammalian central nervous system via the formation of intermediate precursors. Although less frequent, neural stem cells persevere in the postnatal brain where they generate neurons and glia. Adult neurogenesis occurs throughout life in a few limited brain regions. Regulation of neural stem cell number during central nervous system development and in adult life is associated with rigorous control. Failure in this regulation may lead to e.g. brain malformation, impaired learning and memory, or tumor development. Signaling pathways that are perturbed in glioma are the same that are important for neural stem cell self-renewal, differentiation, survival, and migration. The heterogeneity of human gliomas has impeded efficient treatment, but detailed molecular characterization together with novel stem cell-like glioma cell models that reflect the original tumor gives opportunities for research into new therapies. The observation that neural stem cells can be isolated and expanded in vitro has opened new avenues for medical research, with the hope that they could be used to compensate the loss of cells that features in several severe neurological diseases. Multipotent neural stem cells can be isolated from the embryonic and adult brain and maintained in culture in a defined medium. In addition, neural stem cells can be derived from embryonic stem cells and induced pluripotent stem cells by in vitro differentiation, thus adding to available models to study stem cells in health and disease.

Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to promote tissue function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term NSCs (ST-NSCs) and long-term NSCs (LT-NSCs). ST-NSCs divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-NSCs are maintained for months but are pushed out of homeostasis by lengthening quiescence. Single-cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC aging factor. Treatment with the Abl inhibitor imatinib increased NSC activation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable and adaptable to cellular aging.

Stem cells have been used for regenerative and therapeutic purposes in a variety of diseases. In ischemic brain injury, preclinical studies have been promising, but have failed to translate results to clinical trials. We aimed to explore the application of stem cells after ischemic brain injury by focusing on topics such as delivery routes, regeneration efficacy, adverse effects, and in vivo potential optimization. PUBMED and Web of Science were searched for the latest studies examining stem cell therapy applications in ischemic brain injury, particularly after stroke or cardiac arrest, with a focus on studies addressing delivery optimization, stem cell type comparison, or translational aspects. Other studies providing further understanding or potential contributions to ischemic brain injury treatment were also included. Multiple stem cell types have been investigated in ischemic brain injury treatment, with a strong literature base in the treatment of stroke. Studies have suggested that stem cell administration after ischemic brain injury exerts paracrine effects via growth factor release, blood-brain barrier integrity protection, and allows for exosome release for ischemic injury mitigation. To date, limited studies have investigated these therapeutic mechanisms in the setting of cardiac arrest or therapeutic hypothermia. Several delivery modalities are available, each with limitations regarding invasiveness and safety outcomes. Intranasal delivery presents a potentially improved mechanism, and hypoxic conditioning offers a potential stem cell therapy optimization strategy for ischemic brain injury. The use of stem cells to treat ischemic brain injury in clinical trials is in its early phase; however, increasing preclinical evidence suggests that stem cells can contribute to the down-regulation of inflammatory phenotypes and regeneration following injury. The safety and the tolerability profile of stem cells have been confirmed, and their potent therapeutic effects make them powerful therapeutic agents for ischemic brain injury patients.

Anxiety is known to dysregulate the salience, default mode, and central executive networks of the human brain, yet this phenomenon has not been fully explored across the STEM learning experience, where anxiety can impact negatively academic performance. Here, we evaluated anxiety and large-scale brain connectivity in 101 undergraduate physics students. We found sex differences in STEM-related and clinical anxiety, with longitudinal increases in science anxiety observed for both female and male students. Sex-specific relationships between STEM anxiety and brain connectivity emerged, with male students exhibiting distinct inter-network connectivity for STEM and clinical anxiety, and female students demonstrating no significant within-sex correlations. Anxiety was negatively correlated with academic performance in sex-specific ways at both pre- and post-instruction. Moreover, math anxiety in male students mediated the relation between default mode-salience connectivity and course grade. Together, these results reveal complex sex differences in the neural mechanisms driving how anxiety is related to STEM learning.

Brain disorders, from neurodegenerative to psychiatric disorders, are among the most challenging conditions to study because of the intricate nature of the human brain and the limitations of existing model systems in recapitulating all these intricacies. However, innovations in stem cell technologies now allow us to reprogram patient somatic cells to induced pluripotent stem cells (iPSCs), which can then be differentiated to disease-relevant neural and glial cells. iPSCs are a valuable tool to model brain disorders, as they can be derived from patients with known symptom histories, genetics, and drug-response profiles. Here, we discuss the premise and validity of the iPSC-based in vitro model system and highlight key findings from the most commonly studied neurodegenerative and psychiatric disorders.

Cancers are believed to arise from cancer stem cells (CSCs), but it is not known if these cells remain dependent upon the niche microenvironments that regulate normal stem cells. We show that endothelial cells interact closely with self-renewing brain tumor cells and secrete factors that maintain these cells in a stem cell-like state. Increasing the number of endothelial cells or blood vessels in orthotopic brain tumor xenografts expanded the fraction of self-renewing cells and accelerated the initiation and growth of tumors. Conversely, depletion of blood vessels from xenografts ablated self-renewing cells from tumors and arrested tumor growth. We propose that brain CSCs are maintained within vascular niches that are important targets for therapeutic approaches.

Patients with acute central vestibular syndrome suffer from vertigo, spontaneous nystagmus, postural instability with lateral falls, and tilts of visual vertical. Usually, these symptoms compensate within months. The mechanisms of compensation in vestibular infarcts are yet unclear. This study focused on structural changes in gray and white matter volume that accompany clinical compensation.

Brain pericytes play important roles in the formation and maintenance of the neurovascular unit (NVU), and their dysfunction has been implicated in central nervous system disorders. While human pluripotent stem cells (hPSCs) have been used to model other NVU cell types, including brain microvascular endothelial cells (BMECs), astrocytes, and neurons, hPSC-derived brain pericyte-like cells have not been integrated into these models. In this study, we generated neural crest stem cells (NCSCs), the embryonic precursor to forebrain pericytes, from hPSCs and subsequently differentiated NCSCs to brain pericyte-like cells. These cells closely resembled primary human brain pericytes and self-assembled with endothelial cells. The brain pericyte-like cells induced blood-brain barrier properties in BMECs, including barrier enhancement and reduced transcytosis. Last, brain pericyte-like cells were incorporated with iPSC-derived BMECs, astrocytes, and neurons to form an isogenic human model that should prove useful for the study of the NVU.

Rodents shift their nose from side to side when they actively explore and lateralize odors in the space. This motor action is driven by a pair of muscles, the deflector nasi. We studied the premotor control of this motion. We used replication-competent rabies virus to transsynaptically label inputs to the deflector nasi muscle and find putative premotor labeling throughout the parvocellular, intermediate, and gigantocellular reticular formations, as well as the trigeminal nuclei, pontine reticular formation, midbrain reticular formation, red nucleus, and superior colliculus. Two areas with extensive labeling were analyzed for their impact on nose movement. One area is in the reticular formation caudal to the facial motor nucleus and is denoted the nose retrofacial area. The second is in the caudal part of the intermediate reticular region near the oscillator for whisking (the nose IRt). Functionally, we find that optogenetic activation of glutamatergic cells in both areas drives deflection of the nose. Ablation of cells in the nose retrofacial area, but not the nose IRt, impairs movement of the nose in response to the presentation of odorants but otherwise leaves movement unaffected. These data suggest that the nose retrofacial area is a conduit for a sensory-driven orofacial motor action. Furthermore, we find labeling of neurons that are immediately upstream of premotor neurons in the preBötzinger complex that presumably synchronizes a small, rhythmic component of nose motion to breathing. NEW & NOTEWORTHY We identify two previously undescribed premotor areas in the medulla that control deflection of the nose. This includes a pathway for directed motion of the nose in response to an odorant.

Fetal cells can enter maternal blood during pregnancy but whether they can also cross the blood-brain barrier to enter the maternal brain remains poorly understood. Previous results suggest that fetal cells are summoned to repair damage to the mother's brain. If this is confirmed, it would open up new and safer avenues of treatment for brain damage caused by strokes and neural diseases. In this study, we aimed to investigate whether a baby's stem cells can enter the maternal brain during pregnancy. Deceased patients who had at least one male offspring and no history of abortion and blood transfusion were included in this study. DNA was extracted from brain tissue samples of deceased women using standard phenol-chloroform extraction and ethanol precipitation methods. Genomic DNA was screened by quantitative fluorescent-polymerase chain reaction amplification together with short tandem repeat markers specific to the Y chromosome, and 13, 18, 21 and X. Any foreign DNA residues that could be used to interpret the presence of fetal stem cells in the maternal brain were monitored. Results indicated that fetal stem cells can not cross the blood-brain barrier to enter the maternal brain.

Status epilepticus (SE) is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant action.

Brain stroke is the second most important events that lead to disability and morbidity these days. Although, stroke is important, there is no treatment for curing this problem. Nowadays, cell therapy has opened a new window for treating central nervous system disease. In some previous studies the Mesenchymal stem cells and neural stem cells. In this study, we have designed an experiment to assess the combination cell therapy (Mesenchymal and Neural stem cells) effects on brain stroke.

The discovery of stem cells in the adult human brain has revealed new possible scenarios for treatment of the sick or injured brain. Both clinical use of and preclinical research on human adult neural stem cells have, however, been seriously hampered by the fact that it has been impossible to passage these cells more than a very few times and with little expansion of cell numbers. Having explored a number of alternative culturing conditions we here present an efficient method for the establishment and propagation of human brain stem cells from whatever brain tissue samples we have tried. We describe virtually unlimited expansion of an authentic stem cell phenotype. Pluripotency proteins Sox2 and Oct4 are expressed without artificial induction. For the first time multipotency of adult human brain-derived stem cells is demonstrated beyond tissue boundaries. We characterize these cells in detail in vitro including microarray and proteomic approaches. Whilst clarification of these cells' behavior is ongoing, results so far portend well for the future repair of tissues by transplantation of an adult patient's own-derived stem cells.

Limited migration of neural stem cells in adult brain is a roadblock for the use of stem cell therapies to treat brain diseases and injuries. Here, we report a strategy that mobilizes and guides migration of stem cells in the brain in vivo. We developed a safe stimulation paradigm to deliver directional currents in the brain. Tracking cells expressing GFP demonstrated electrical mobilization and guidance of migration of human neural stem cells, even against co-existing intrinsic cues in the rostral migration stream. Transplanted cells were observed at 3 weeks and 4 months after stimulation in areas guided by the stimulation currents, and with indications of differentiation. Electrical stimulation thus may provide a potential approach to facilitate brain stem cell therapies.

Fossils provide insights into how organs may have diversified over geological time.1 However, diversification already accomplished early in evolution can obscure ancestral events leading to it. For example, already by the mid-Cambrian period, euarthropods had condensed brains typifying modern mandibulate lineages.2 However, the demonstration that extant euarthropods and chordates share orthologous developmental control genes defining the segmental fore-, mid-, and hindbrain suggests that those character states were present even before the onset of the Cambrian.3 Fossilized nervous systems of stem Euarthropoda might, therefore, be expected to reveal ancestral segmental organization, from which divergent arrangements emerged. Here, we demonstrate unsurpassed preservation of cerebral tissue in Kaili leanchoiliids revealing near-identical arrangements of bilaterally symmetric ganglia identified as the proto-, deuto-, and tritocerebra disposed behind an asegmental frontal domain, the prosocerebrum, from which paired nerves extend to labral ganglia flanking the stomodeum. This organization corresponds to labral connections hallmarking extant euarthropod clades4 and to predicted transformations of presegmental ganglia serving raptorial preocular appendages of Radiodonta.5 Trace nervous system in the gilled lobopodian Kerygmachela kierkegaardi6 suggests an even deeper prosocerebral ancestry. An asegmental prosocerebrum resolves its location relative to the midline asegmental sclerite of the radiodontan head, which persists in stem Euarthropoda.7 Here, data from two Kaili Leanchoilia, with additional reference to Alalcomenaeus,8,9 demonstrate that Cambrian stem Euarthropoda confirm genomic and developmental studies10-15 claiming that the most frontal domain of the euarthropod brain is a unique evolutionary module distinct from, and ancestral to, the fore-, mid-, and hindbrain.

Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain.

Glioma incidence rates in the United States are near 20000 new cases per year, with a median survival time of 14.6 mo for high-grade gliomas due to limited therapeutic options. The origins of these tumors and their many subtypes remain a matter of investigation. Evidence from mouse models of glioma and human clinical data have provided clues about the cell types and initiating oncogenic mutations that drive gliomagenesis, a topic we review here. There has been mixed evidence as to whether or not the cells of origin are neural stem cells, progenitor cells or differentiated progeny. Many of the existing murine models target cell populations defined by lineage-specific promoters or employ lineage-tracing methods to track the potential cells of origin. Our ability to target specific cell populations will likely increase concurrently with the knowledge gleaned from an understanding of neurogenesis in the adult brain. The cell of origin is one variable in tumorigenesis, as oncogenes or tumor suppressor genes may differentially transform the neuroglial cell types. Knowledge of key driver mutations and susceptible cell types will allow us to understand cancer biology from a developmental standpoint and enable early interventional strategies and biomarker discovery.

There is compelling evidence that brain tumors, particularly glioblastoma multiforme (GBM), harbor a small population of cancer stem cells (CSCs). These CSCs have the ability to undergo self-renewal, initiate tumors in vivo, and are resistant to chemotherapy and radiation therapy. The present study determined the spatial distribution of CSCs within the donated brains of two deceased patients affected by glioblastoma multiforme. The following six grossly visible functional regions were identified: Necrotic tumor, viable solid tumor, infiltrating tumor edge, peritumoral normal brain, normal brain close to the tumor and normal brain distant from the tumor. Each region was snap-frozen, sectioned and immunostained for the CSC biomarkers prominin-1 (CD133) and sex-determining region Y-box 2 (SOX2). The percentages of CD133+ and SOX2+ cells within each region were determined. Different percentages of CD133+ and SOX2+ cells were identified in different regions. Significantly higher percentages of CD133+ and SOX2+ cells were indicated at the infiltrating tumor edge when compared with other areas. In summary, the spatial distributions of CSCs in these two brains with glioblastoma multiforme were similar, with the highest concentration being at the infiltrating tumor edge. This suggests that the edge of the tumor is the moving front for tumor progression and invasion, and should be targeted for therapeutic intervention.