During embryonic development, radial glial precursor cells give rise to neural lineages, and a small proportion persist in the adult mammalian brain to contribute to long-term neuroplasticity. Neural stem cells (NSCs) reside in two neurogenic niches of the adult brain, the hippocampus and the subventricular zone (SVZ). NSCs in the SVZ are endowed with the defining stem cell properties of self-renewal and multipotent differentiation, which are maintained by intrinsic cellular programs, and extrinsic cellular and niche-specific interactions. In glioblastoma, the most aggressive primary malignant brain cancer, a subpopulation of cells termed glioblastoma stem cells (GSCs) exhibit similar stem-like properties. While there is an extensive overlap between NSCs and GSCs in function, distinct genetic profiles, transcriptional programs, and external environmental cues influence their divergent behavior. This review highlights the similarities and differences between GSCs and SVZ NSCs in terms of their gene expression, regulatory molecular pathways, niche organization, metabolic programs, and current therapies designed to exploit these differences.

In vitro tests are increasingly applied in chemical hazard assessment. Basic culture conditions may affect the outcome of in vitro tests and should be optimised to reduce false predictions. The neural embryonic stem cell test (ESTn) can predict early neurodevelopmental effects of chemicals, as it mimics the differentiation of stem cells towards the neuroectodermal lineage. Normal early neural differentiation depends crucially on folic acid (FA) and methionine (MET), both elements of the one-carbon (1C) cycle. The aim of this study was to assess the concentration-dependent influence of FA and MET on neural differentiation in the ESTn, and its consequences for assay sensitivity to methotrexate (MTX), a compound that interferes with the 1C cycle. Neural differentiation was inhibited below 0.007 mM and above 0.22 mM FA, while both stem cell viability (< 0.097 mM, > 1.52 mM) and neural differentiation (< 0.181 mM, > 1.35 mM) were affected when changing MET concentrations. A 10-day exposure to 13 nM MTX inhibited neural differentiation, especially in FA- and MET-deficient conditions. However, a 24-hour exposure to 39 nM MTX decreased neural cell and neural crest cell differentiation markers only when the concentration of FA in the medium was three times the standard concentration, which was expected to have a protective effect against MTX. These results show the importance of nutrient concentrations, exposure scenarios and timing of read-outs for cell differentiation and compound sensitivity in the ESTn. Caution should be taken when interpreting results from a single in vitro test, especially when extrapolating to effects on complex morphogenetic processes, like neural tube development.

Patients with chronic stroke have currently little hope for motor improvement towards regaining independent activities of daily living; stem cell treatments offer a new treatment option and needs to be developed. Patients with chronic stroke (more than 3 months prior to stem cell treatment, mean 21.2 months post-stroke) were treated with CD271+ stem cells, 7 patients received autologous and 1 allogeneic cells from first degree relative; administration was intravenous in 1 and intrathecal in 7 patients. Each patient received a single treatment consisting of 2-5x106 cells/kg and they were followed up for up to 12 months. There were significant improvements in expressive aphasia (2/3 patients) spasticity (5/5, of which 2 were transient), and small improvements in motor function (2/8 patients). Although motor improvements were minor in our chronic stroke patients, improvements in aphasia and spasticity were significant and in the context of good safety we are advocating further administration and clinical studies of CD271+ stem cells not only in chronic stroke patients, but also for spastic paresis/plegia; a different, yet unexplored application is pulmonary emphysema.

Using human induced pluripotent stem cells (iPSC), recent studies have shown that the events underlying autism spectrum disorders (ASD) can occur during neonatal development. We previously analyzed the iPSC-derived pyramidal cortical neurons of a subset of patients with ASD carrying de novo heterozygous mutations in postsynaptic SHANK3 protein, in culture. We reported altered spinogenesis of those neurons. The transplantation of human iPSC-derived neuronal precursors into mouse brain represents a novel option for in vivo analysis of mutations affecting the human brain. In this study, we transplanted the neuronal precursor cells (NPC) into the cortex of newborn mice to analyze their integration and maturation at early stages of development and studied axonal projections of transplanted human neurons into adult mouse brain. We then co-transplanted NPC from a control individual and from a patient carrying a de novo heterozygous SHANK3 mutation. We observed a reduction in cell soma size of selective neuronal categories and in axonal projections at 30 days post-transplantation. In contrast to previous in vitro studies, we did not observe any alteration in spinogenesis at this early age. The humanized chimeric mouse models offer the means to analyze ASD-associated mutations further and provide the opportunity to visualize phenotypes in vivo.

The Scribble polarity module is composed by Scribble (Scrib), Discs large 1 (Dlg1) and Lethal (2) giant larvae (L(2)gl), a group of highly conserved neoplastic tumor suppressor genes (TSGs) from flies to humans. Even though the Scribble module has been profusely studied in epithelial cell polarity, the number of tissues and processes in which it is involved is increasingly growing. Here we discuss the role of the Scribble module in the asymmetric division of Drosophila neuroblasts (NBs), as well as the underlying mechanisms by which those TSGs act in this process. Finally, we also describe what we know about the consequences of mutating these genes in impairing the process of asymmetric NB division and promoting tumor-like overgrowth.

Individuals with Parkinson\'s disease (PD) suffer from motor and mental disturbances due to degeneration of dopaminergic and non-dopaminergic neuronal systems. Although they provide temporary symptom relief, current treatments fail to control motor and non-motor alterations or to arrest disease progression. Aiming to explore safety and possible motor and neuropsychological benefits of a novel strategy to improve the PD condition, a case series study was designed for brain grafting of human neural progenitor cells (NPCs) to a group of eight patients with moderate PD. A NPC line, expressing Oct-4 and Sox-2, was manufactured and characterized. Using stereotactic surgery, NPC suspensions were bilaterally injected into patients\' dorsal putamina. Cyclosporine A was given for 10 days prior to surgery and continued for 1 month thereafter. Neurological, neuropsychological, and brain imaging evaluations were performed pre-operatively, 1, 2, and 4 years post-surgery. Seven of eight patients have completed 4-year follow-up. The procedure proved to be safe, with no immune responses against the transplant, and no adverse effects. One year after cell grafting, all but one of the seven patients completing the study showed various degrees of motor improvement, and five of them showed better response to medication. PET imaging showed a trend toward enhanced midbrain dopaminergic activity. By their 4-year evaluation, improvements somewhat decreased but remained better than at baseline. Neuropsychological changes were minor, if at all. The intervention appears to be safe. At 4 years post-transplantation we report that undifferentiated NPCs can be delivered safely by stereotaxis to both putamina of patients with PD without causing adverse effects. In 6/7 patients in OFF condition improvement in UPDRS III was observed. PET functional scans suggest enhanced putaminal dopaminergic neurotransmission that could correlate with improved motor function, and better response to L-DOPA. Patients\' neuropsychological scores were unaffected by grafting. Trial Registration: Fetal derived stem cells for Parkinson\'s disease https://doi.org/10.1186/ISRCTN39104513Reg#ISRCTN39104513.

The alterations that underlie the pathophysiology of schizophrenia (SCZ) include the dysregulation of structural and functional properties of neurons. Among these, the secretion of neurotransmitters and hormones, which plays a key role for neuronal communication and development, is altered. Neuronal precursors from the human olfactory epithelium have been recently characterized as a reliable model for studying the etiopathogenesis of neuropsychiatric diseases. Our previous work has shown that melatonin enhances the development of morphological and functional features of cloned olfactory neuronal precursors (ONPs) from a healthy subject. In this work we found that primary cultures of ONPs obtained from a schizophrenic patient display an increased potassium-evoked secretion, when compared with ONPs from an age- and gender-matched healthy control subject (HCS). Secretion was evaluated by FM1-43 fluorescence cumulative changes in response to depolarization. Interestingly, a 12 h-melatonin treatment modulated the abnormally increased secretion in SCZ ONPs and brought it to levels similar to those found in the HCS ONPs. Our results suggest that the actin cytoskeleton might be a target for melatonin effects, since it induces the thickening of actin microfilament bundles. Further research will address the mechanisms by which melatonin modulates neurochemical secretion from ONPs.

Glioblastoma is the most common and aggressive adult brain tumour. Over the last 10 years it has emerged that the subventricular zone (SVZ), the largest adult neural stem cell niche, has an important role in the disease. Converging evidence has implicated transformation of adult neural stems in gliomagenesis and the permissive stem cell niche in disease recurrence. Concurrently, clinical studies have suggested that SVZ involvement is a negative prognostic marker. It would follow that irradiating the SVZ may improve outcomes in glioblastoma by directly targeting this putative sanctuary site. To investigate this potential strategy, 11 retrospective studies and 1 prospective study examined the relationship between dose to the SVZ and survival outcomes in glioblastoma patients. This review summarises the theoretical underpinning of this strategy, provides a critical evaluation of the existing evidence and discusses the rationale for a clinical trial.

Primary torsion dystonia (PTD) occurs due to a genetic mutation and often advances gradually. Currently, there is no therapy available that is able to inhibit progression. Neural stem cells (NSCs) are being investigated as potential therapies for neurodegenerative diseases, such as stroke and trauma. The present study evaluated the clinical effectiveness of NSC transplantation in an 18-year-old male patient with PTD, to assess the ability of this therapy to inhibit PTD progression. Genetic testing of the patient revealed a mutation in the torsion dystonia-1 (DYT1) gene (907-909 delGAG). NSCs were bilaterally implanted in the globus pallidus of the patient through stereotactic surgery. Prior to surgery, the patient\'s Burke-Fahn-Marsden dystonia movement score (BFMDMS) was 21, which progressively decreased after surgery to 18, 17, 15 and 13 at 1, 2, 3 and 4 postoperative years, respectively. BFMDMS was improved by 38.1% over the 4 postoperative years. Although computed tomography and magnetic resonance imaging examinations showed no significant changes prior to and following surgery, postoperative brain positron emission tomography scans revealed increased glucose metabolism in the transplanted region. The clinical efficacy of NSC transplantation in this patient suggests its potential for the treatment of DYT1-positive patients with PTD.

We compared the characteristics of neural cells derived from induced pluripotent stem (iPS) cells from a patient with multiple sclerosis versus neurally differentiated control iPS cells of a healthy individual. The iPS cells were differentiated toward the oligodendrocyte lineage using a four-step protocol established for the differentiation of embryonic stem cells. The resulting cell population was immunostained on day 112 of differentiation for the presence of oligodendrocytes and analyzed by transmission electron microscopy (TEM). Both patient and control samples resembled a mixed population of neural cells rather than oligodendroglia of high purity, including neural stem cell-like cells and possibly oligodendrocytes demonstrable by TEM.