The Crossroads of Neural Stem Cell Development and Tumorigenesis.

Stem cells are unique cells that possess the capacities to both self-renew and give rise to multiple differentiated progeny. There exist two major types of stem cells that help to create the nervous system: CNS stem cells which produce the neurons and glia of the central nervous system and neural crest cells which produce not only the neurons and glia of the peripheral nervous system, but also structures such as the craniofacial skeleton, cardiac outflow tracts, skin pigment cells, and sympathoadrenal cells. The mechanisms of self-renewal, migration, and differentiation of these two stem cell types have been studied in great detail. Yet despite such insight, much remains to be known about key aspects of neural stem cell development. First, it has long been thought that there might be a lineal relationship between CNS stem cells in human embryos or adults and primary brain tumors, particularly those malignancies occurring in children. To earn better insight into this possibility, I examined fresh pediatric brain tumors and found that they contained a subpopulation of cells with characteristics of neural stem cells that, at a clonal level, could recapitulate properties of the parental tumor. These tumor-derived progenitors shared genetic similarities with normal neural stem cells and could migrate and proliferate in vivo. Second, I have studied whether the late-migrating wave of neural crest cells and their derivatives originates from stem or progenitor cells resident in the embryonic spinal cord by culturing quail neural tube cells as neurospheres. I have found that these cells have the potential to generate melanocytes and possibly other neural crest derivatives both in vivo and in vitro after weeks in culture, suggesting that neural crest or melanocytic progenitor cells in the neural tubes of older embryos might contribute to the late-migrating neural crest populations. Taken together, my results in both model systems suggest that neural stem or progenitor cells that persist in the animal beyond early embryonic development play significant roles at later points in development and life, particularly in the continued development of the peripheral nervous system and the development of malignancies of the central nervous system.

The Incredible Elastic Brain: How Neural Stem Cells Expand Our Minds

SummaryThe consequences of DNA damage generation in mammalian somatic stem cells, including neural stem cells (NSCs), are poorly understood despite their potential relevance for tissue homeostasis. Here, we show that, following ionizing radiation-induced DNA damage, NSCs enter irreversible proliferative arrest with features of cellular senescence. This is characterized by increased cytokine secretion, loss of stem cell markers, and astrocytic differentiation. We demonstrate that BMP2 is necessary to induce expression of the astrocyte marker GFAP in irradiated NSCs via a noncanonical signaling pathway engaging JAK-STAT. This is promoted by ATM and antagonized by p53. Using a SOX2-Cre reporter mouse model for cell-lineage tracing, we demonstrate irradiation-induced NSC differentiation in vivo. Furthermore, glioblastoma assays reveal that irradiation therapy affects the tumorigenic potential of cancer stem cells by ablating self-renewal and inducing astroglial differentiation.

H3.3-K27M drives neural stem cell-specific gliomagenesis in a human iPSC-derived model.

Age‐related decline in neurogenesis: Old cells or old environment?

It has been suggested that intrinsic brain tumours originate from a neural stem/progenitor cell population in the subventricular zone of the post-natal brain. However, the influence of the initial genetic mutation on the phenotype as well as the contribution of mature astrocytes to the formation of brain tumours is still not understood. We deleted Rb/p53, Rb/p53/PTEN or PTEN/p53 in adult subventricular stem cells; in ectopically neurografted stem cells; in mature parenchymal astrocytes and in transplanted astrocytes. We found that only stem cells, but not astrocytes, gave rise to brain tumours, independent of their location. This suggests a cell autonomous mechanism that enables stem cells to generate brain tumours, whereas mature astrocytes do not form brain tumours in adults. Recombination of PTEN/p53 gave rise to gliomas whereas deletion of Rb/p53 or Rb/p53/PTEN generated primitive neuroectodermal tumours (PNET), indicating an important role of an initial Rb loss in driving the PNET phenotype. Our study underlines an important role of stem cells and the relevance of initial genetic mutations in the pathogenesis and phenotype of brain tumours.

Translating Stem Cell Studies to the Clinic for CNS Repair: Current State of the Art and the Need for a Rosetta Stone

Home at Last: Neural Stem Cell Niches Defined

The development of neural stem cells is regulated by a variety of growth and cell adhesion factors. A promising approach to direct their differentiation in vitro is the generation of cell substrates that replicate the intricate physical and biochemical properties of their cellular environment. The primary aim of this work was to develop cell substrates that mimic these properties and explore their potential in directing the differentiation of embryonic neural stem cells and in supporting axonal outgrowth. For this, gold nanopatterned glass substrates were used for the controlled immobilization of proteins. The resulting substrates feature nanopatterned cell signaling proteins at variable surface density, as well as additional cell adhesive molecules. The role of both factors in regulating the differentiation of mouse embryonic neural stem cells was investigated independently. Differentiation of neural stem cells on substrates uniformly coated with the cell adhesion molecules laminin, fibronectin and N-cadherin showed no effect on the in vitro generation of newborn neurons in comparison to polyornithine controls. Moreover, a 2,5-fold increase in cell number was observed on all cell-adhesion molecules, indicating an increase in cell proliferation. Furhermore, the role of cell adhesion molecules in supporting axonal outgrowth of dorsal root ganglia explants was investigated. The longest axonal projections ranging up to 800µm could be observed on laminin-coated substrates. In contrast, outgrowth on fibronectin as well as fibronectin-derived peptide nanopatterned substrates resulted in 200-250µm long projections. The role of nanopatterned Notch cell receptor ligand Delta-like 1 (Dll-1) substrates in directing the differentiation of neural stem cell cultures was investigated using variable ligand densities. As a result, Notch activation resulted in increased neurite number, branching, and cell body size. The strongest response was observed using 340 ligands/µm2 (56nm interparticle spacing) in comparison to 735 ligand/µm2 (90nm) and uniformly coated Dll-1 substrates. Additionally, a small fraction of drastically enlarged neurons was observed on Dll-1 substrates, but no effect on the total number of newborn neurons. The next aim of this thesis was to develop a system for the non-invasive visualization of the embryonic nervous system. For this, a transgenic mouse line that expresses high levels of green fluorescent protein (GFP) specifically in newborn neurons was characterized. Imaging using light sheet fluorescence microscopy resulted in high- resolution visualization of the entire nervous system in whole embryos allowing for generation of three-dimensional models and virtual specimen sectioning. Additionally, this technique was successfully applied for the visualization of innervation defects caused by mutation of the axonal-guidance protein Semaphorin 3A. In summary, the nanopatterned protein substrates presented in this work constitute a powerful tool for influencing in vitro development of neural stem cells. Additionally, the introduced transgenic mouse featuring GFP-expressing neurons allows for highly detailed visualization of the developing nervous system in whole embryos.

Tuberous sclerosis complex (TSC) is a relatively rare genetic disease characterized by the formation of benign tumors or hamartomas in multiple organs. The tumors are noninvasive and rarely transform to metastatic lesions. TSC is an autosomal dominant disorder that results from mutations in the TSC1 or TSC2 genes. Neurologically, individuals with TSC have severe complications, including refractory seizures, autism, mental retardation, learning difficulties, and changes in behavior. Tubers in the cerebral cortex, subependymal nodules (SENs) along the lateral walls of the lateral ventricles, and subependymal giant cell (GC) astrocytomas are characteristic brain lesions in patients with TSC. Astrocytic-like cells immunopositive for both glial and neuronal markers, dysplastic neurons (DNs), and GCs immunopositive for nestin and vimentin, as well as for proliferation markers such as proliferating nuclear cell antigen (PCNA) and Ki-67, are histological hallmarks of the disease. DNs and GCs retain their ability to re-enter the cell cycle and are immunopositive for markers of neural progenitor and stem cells. Neurogenesis occurs in the adult brain of mammals, particularly in the hippocampus and subventricular zone (SVZ). In the SVZ, newly generated neuronal cells migrate along the ventricle and a SVZ origin for brain tumors in the adult brain have been reported. These brain tumors express markers of neural progenitor and stem cells. The study of analogies and differences between SENs in TSC, neurogenesis in the SVZ, and tumors in the adult brain would reveal clues on the development and origin of SENs and brain tumors. Keywords: Epilepsy, Cancer, Drug, Disease, Neural stem cells, Rapamycin, Therapy, Tumor DOI:10.5055/jndr.2013.0012

Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans.

Ubiquitin ligases are central components of the ubiquitin-proteasome system (UPS), the major machinery for regulated proteolysis in eukaryotic cells. Proteins essential for regulating development, differentiation, proliferation, cell cycling, apoptosis, gene transcription, and signal transduction undergo posttranslational processing via selection by ubiquitin ligases and subsequent controlled proteolysis by the 26S proteasome, the proteolytic unit of the UPS. Neural stem cells (NSCs) are self-renewing multipotent cells of the embryonic and adult mammalian central nervous system. In the last few years, NSCs have generated considerable interest because of their potential to repair neurological damage in preclinical models of stroke, spinal cord injury, and neurodegenerative disease. Recent evidence reveals a central role of ubiquitin ligases in controlling the development, survival, differentiation, and programming of neural stem and progenitor cells. Here the current knowledge of the role and function of ubiquitin ligases in neural stem and progenitor cells is reviewed and insight into an important mechanism of NSC homeostasis by regulated proteolysis is provided.

EDITORIAL article Front. Cell. Neurosci., 19 January 2016Sec. Cellular Neurophysiology Volume 9 - 2015 | https://doi.org/10.3389/fncel.2015.00504

Translation: Screening for Novel Therapeutics With Disease-Relevant Cell Types Derived from Human Stem Cell Models

Robust In Vivo Transduction of Nervous System and Neural Stem Cells by Early Gestational Intra Amniotic Gene Transfer Using Lentiviral Vector