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Induced neural stem cells (iNSCs), which have similar properties to neural stem cells and are able to self-proliferate and differentiate into neural cell lineages, are expected to be potential cells for the treatment of neurodegeneration disease. However, cell therapy based on iNSCs transplantation is limited by the inability to acquire sufficient quantities of iNSCs. Previous studies have found that mouse and human fibroblasts can be directly reprogrammed into iNSCs with a single factor, Sox2. Here, we induced mouse embryonic fibroblasts (MEFs) into iNSCs by combining valproic acid (VPA) with the induction factor Sox2, and the results showed that VPA significantly improved the conversion efficiency of fibroblasts to iNSCs. The iNSCs exhibited typical neurosphere-like structures that can express NSCs markers, such as Sox2, Nestin, Sox1, and Zbtb16, and could differentiate into neurons, astrocytes, and oligodendrocytes in vitro. Subsequently, the iNSCs were stereotactically transplanted into the hippocampus of APP/PS1 double transgenic mice (AD mice). Post-transplantation, the iNSCs showed long-term survival, migrated over long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Importantly, the cognitive abilities of APP/PS1 mice transplanted with iNSCs exhibited significant functional recovery. These findings suggest that VPA enhances the conversion efficiency of fibroblasts into iNSCs when used in combination with Sox2, and iNSCs hold promise as a potential donor material for transplantation therapy in Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Abstract Induced neural stem cells (iNSCs), which have similar properties to neural stem cells and are able to self-proliferate and differentiate into neural cell lineages, are expected to be potential cells for the treatment of neurodegeneration disease. However, cell therapy based on iNSCs transplantation is limited by the inability to acquire sufficient quantities of iNSCs. Previous studies have found that mouse and human fibroblasts can be directly reprogrammed into iNSCs with a single factor, Sox2. Here, we induced mouse embryonic fibroblasts (MEFs) into iNSCs by combining valproic acid (VPA) with the induction factor Sox2, and the results showed that VPA significantly improved the conversion efficiency of fibroblasts to iNSCs. The iNSCs exhibited typical neurosphere-like structures that can express NSCs markers, such as Sox2, Nestin, Sox1, and Zbtb16, and could differentiate into neurons, astrocytes, and oligodendrocytes in vitro. Subsequently, the iNSCs were stereotactically transplanted into the hippocampus of APP/PS1 double transgenic mice (AD mice). Post-transplantation, the iNSCs showed long-term survival, migrated over long distances, and differentiated into multiple types of functional neurons and glial cells in vivo. Importantly, the cognitive abilities of APP/PS1 mice transplanted with iNSCs exhibited significant functional recovery. These findings suggest that VPA enhances the conversion efficiency of fibroblasts into iNSCs when used in combination with Sox2, and iNSCs hold promise as a potential donor material for transplantation therapy in Alzheimer’s disease.

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

Brain inflammation causes cell damage and death in diseases such as Alzheimer's and Parkinson's. In this study, we investigated whether early induced neural stem cells (iNSCs) could protect against cell death after treatment with THP1-derived macrophages. We developed an inflammatory model system with THP1-derived macrophages and cortical neuronal cells and investigated the therapeutic efficacy of iNSC against macrophage-induced inflammation in this model. Apoptosis was confirmed by double immunocytochemistry with NeuN and 4′,6-diamidino-2-phenylindole using terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling. Cortical neuronal cells cultured with iNSCs exhibited fewer apoptotic cells than did cultures without iNSCs. The levels of inflammatory cytokines and vascular endothelial growth factor (VEGF) were analyzed by enzyme-linked immunosorbent assay. Cells cultured with iNSCs had lower levels of inflammatory cytokines and higher VEGF levels than those cultured without iNSCs. Western blot analysis for cyclooxygenase-2 (COX-2) showed a significantly lower level of COX-2 in cells cultured with iNSCs than in those cultured without iNSCs. Thus, early iNSCs administration reduced inflammation associated with neurological recovery, and this effect is mediated by COX-2 regulation. Our results suggest that iNSCs have potential therapeutic relevance, because they display strong anti-inflammatory functions that promote neuroprotection thorough the inflammatory response. [ABSTRACT FROM AUTHOR]

Highlights: [•] We compare several approaches to obtain induced neural stem cells from fibroblasts. [•] We propose a possible list of features to define induced neural stem cells. [•] We review alternative approaches in fibroblasts transdifferentiation. [•] We discuss advantages of induced neural stem cells for clinical uses. [Copyright &y& Elsevier]

Recent advances in somatic cell reprogramming is one of the most important developments in neuroscience in the last decades since it offers for the first time the opportunity to work with disease/patient-specific neurons or other neural cell types. Induced pluripotent stem cells (iPSCs) can be differentiated into all cell types of the body enabling investigations not only on neurons but also on muscle or endothelial cells which are cell types often also of great interest in neurodegenerative diseases. The novel technology of direct lineage conversion of somatic cells into neurons (induced neurons; iNs) or into expandable multipotent neural stem cells (induced neural stem cells; iNSCs) provides interesting alternatives to the iPSC technology. These techniques have the advantage of easier cell culture, but only neurons (iNs) or neuroectodermal cells (iNSCs) can be generated. Although there are several open questions coming along with these new neural cell types, they hold great promises for both cell replacement and cell modelling of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Cell fate reprogramming makes possible the generation of new cell types from healthy adult cells to replace those lost or damaged in disease. Additionally, reprogramming patient cells into specific cell types allows for drug screening and the development of new therapeutic tools. Generation of new neurons is of particular interest because of the potential to treat diseases of the nervous system, such as neurodegenerative disorders and spinal cord injuries, with cell replacement therapy. Recent advances in cell fate reprogramming have led to the development of novel methods for the direct conversion of fibroblasts into neurons and neural stem cells. This review will highlight the advantages of these new methods over neuronal induction from embryonic stem cells and induced pluripotent stem cells, as well as outline the limitations and the potential for future applications. [ABSTRACT FROM AUTHOR]

Background: The induced neural stem cells (iNSCs) held great promises for cell replacement therapy, but iNSCs modulation need improvement. Matrix stiffness could control stem cell fates and might be effective to iNSCs modulations. Here the stiffness of hydrogel matrix on the adhesion, proliferation and differentiation of iNSCs were studied., Methods: Hyaluronic acid (HA) hydrogels with gradient stiffness were prepared. The structure and stiffness of hydrogels were detected by scanning electron microscopy (SEM) and rheological test. iNSCs were generated from human blood mononuclear cells and cultured in the hydrogels. The cell adhesion, proliferation and differentiation on gradient stiffness hydrogels were examined by CCK-8 test and immunofluorescence staining., Results: All hydrogels showed typical soft tissue, with the elastic modulus increasing with concentration (0.6-1.8%), ranging from 17 to 250 Pa. The iNSCs maintained growth and differentiation on all gels, but showed different behaviors to different stiffness. On the softer hydrogels, cells grew slowly at first but continuously and fast for long term, tending to differentiate into neurons; while on the harder hydrogels, cells adhered and grew faster at the early stage, tending to differentiate into glia cells after long term culture., Conclusions: The results suggested that hydrogels stiffness could regulate the key cellular processes of iNSCs. It was important for iNSCs modulation and application in the future., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-6189). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner. [ABSTRACT FROM AUTHOR]