Meninges as a niche for stem/precursor cells with neural differentiation potential during development up to adulthood
Ilaria DecimoFrancesco BifariMarijana KusaloValeria BertonAnnachiara PinoGiorgio MalpeliMauro KramperaGuido Francesco Fumagalli
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Neural stem cells are a subtype of progenitor cells in the nervous system that can selfrenew and generate neurons, astrocytes, and oligodendrocytes. Stem cells have been isolated from many regions of the embryonic nervous system. Recent studies reveled that adult neural stem cells exist in the adult neurogenic regions, the hippocampus and the subventricular zone, and in some non -neurogenic regions, including spinal cord. Now, neural stem cells can be isolated and cultured as floating, multicellular neurospheres. This review summarizes isolation methods for neural stem cells and the regulatory mechanisms of neural differentiation. The potential therapeutic uses of neural stem cells are also discussed.
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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.
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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.
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Recent studies show that adult neural tissues can harbor stem cells within unique niches. In the mammalian central nervous system, neural stem cell (NSC) niches have been identified in the dentate gyrus and the subventricular zone (SVZ). Stem cells in the well-characterized SVZ exist in a microenvironment established by surrounding cells and tissue components, including transit-amplifying cells, neuroblasts, ependymal cells, blood vessels, and a basal lamina. Within this microenvironment, stem cell properties, including proliferation and differentiation, are maintained. Current NSC culture techniques often include the addition of molecular components found within the in vivo niche, such as mitogenic growth factors. Some protocols use bio-scaffolds to mimic the physical growth environment of living tissue. We describe a novel NSC culture system, derived from embryonic stem (ES) cells, that displays elements of an NSC niche in the absence of exogenously applied mitogens or complex physical scaffolding. Mouse ES cells were neuralized with retinoic acid and plated on an entactin-collagen-laminin-coated glass surface at high density (250,000 cells/cm(2)). Six to eight days after plating, complex multicellular structures consisting of heterogeneous cell types developed spontaneously. NSC and progenitor cell proliferation and differentiation continued within these structures. The identity of cellular and molecular components within the cultures was documented using RT-PCR, immunocytochemistry, and neurosphere-forming assays. We show that ES cells can be induced to form structures that exhibit key properties of a developing NSC niche. We believe this system can serve as a useful model for studies of neurogenesis and stem cell maintenance in the NSC niche as well as for applications in stem cell transplantation.
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