Neural stem cell heterogeneity

International audienceThe ‘identity’ of the neural stem cell (NSC) in the adult mammalian brain has captivated the interest and imagination of scientists since the seminal findings in the 1990s revealing the existence of a unique subset of glial-like cells that fulfill the stem cell criteria of self-renewal and multipotentality. That work was followed by over a decade of unprecedented insight, where the morphological and molecular profiles of these NSCs, their regulation by the tissue microenvironment (or niche) they inhabit, and their potential functional role in mediating behavior, were revealed. These striking revelations about the nature of NSCs have led to a broader interest from the neurobiology community to address the extent to which the properties of NSCs identified in the mammalian (primarily rodent) brain have been conserved in vertebrate evolution. In the last 5 years or so, research in non-mammalian vertebrates has shown that, while some NSC properties appear to be conserved, there are intriguing disparities that have emerged in the data. These include: distinct regenerative properties that are not apparent in mammalian NSCs; distinct attributes of the stem cell niche that do not align with observations from the two most studied neurogenic niches in rodents – the forebrain subventricular zone (SVZ) and the hippocampal subgranular zone (SGZ); and even the existence of different types of adult NSCs with contrasting morphologies, molecular profiles, and perhaps functional roles in the brain. We believe that by bringing together a group of leading neurobiologists in the field to contribute to a Special Issue on the heterogeneous nature of adult vertebrate NSCs, we could enrich our contemporary perspective on the properties of adult NSCs and how adaptions in different species have diversified these properties. Another important impact would be in the area of regenerative medicine. A common desire among clinician-scientists is to harness the regenerative power of NSCs in animal models and apply this to human neural regeneration. The authors contributing to this Special Issue have, indeed, fulfilled these objectives. It is widely believed that NSCs transit through active and quiescent states throughout life, responding to the demands of tissue development or adult neurogenic plasticity. We learn from Adams and Morshead that there may be at least two subpopulations of mammalian NSCs, primitive and definitive, that are lineage related and have what appear to be distinct roles in maintaining neurogenesis in the brain and responding to damage. The notion that NSCs exist as distinct sub-populations raises the possibility that rather than different proliferative states of the same cell, it may be that different subsets of very slow or relatively fast dividing NSCs exist. Bardella, Al-Shammari, Soares and colleagues explain how the SVZ exhibits constitutive semi-activated inflammatory regulation unlike surrounding brain tissue. This has led to the notion that inflammatory responses to damage within the SVZ niche may be different relative to the rest of the brain and may also underlie the susceptibility of SVZ tumorigenesis. The identity of the tumor initiating cells in subependymomas or gliomas remains elusive, but evidence suggests that different NSCs or their progeny could serve as cancer stem cells that form tumors with different degrees of growth and invasiveness. Yoo and Blackshaw inform us that the postnatal mouse hypothalamus harbors various subpopulations of tanycytes, which exhibit radial-glial like NSC characteristics similar to the NSCs found in the SVZ, or Müller cells in the retina, and can give rise to neurons in vivo. The authors explain how these distinct tanycyte sub-populations might contribute to the process of neurogenesis that, in turn, regulates energy homeostasis, body temperature, and reproductive behavior. Becker and colleagues compare the cellular and molecular responses of the spinal cord ventricular zone (VZ) between anamniotes and mammals in order to derive general principles of regenerative neurogenesis. One example involves the ependymo-radial glial (ERG) cell in the zebrafish spinal cord. The ERG cells not only serve to promote axon growth of neurons, but also serve as a multipotent NSC population that can regenerate spinal cord tissue in response to damage. Mouse spinal cord ependymal zone cells with characteristics of NSCs have been identified and these cells increase in proliferation in response to injury, but unlike their properties in vitro, these cells are biased to generate glial cells (primarily astrocytes) in vivo. The authors offer intriguing insight into the differences between the human spinal cord and that of regenerative species like zebrafish that might explain why cells with NSC characteristics fail to mount an in vivo regenerative response. Joven and Simon reveal how homeostatic neurogenesis in the postembryonic brain varies in different species of salamander, some of which have little to no neurogenesis in older stages of life. Despite this variation, most species are capable of mounting a regenerative response in the CNS mediated by the proliferation of brain ependymoglial cells or spinal cord ependymal cells. Interestingly, the presence of reactive oxygen species at sites of injury is critical for this regenerative response, which seems to correlate with some animals adapting to variable oxygen levels in their natural habitat. It is possible that such “local” adaptation of cells with NSC properties in some vertebrate species could provide new insight into ways of manipulating NSCs in others. Like in the mammalian forebrain, there may be at least two distinct types of ependymoglial NSCs that are either relatively quiescent (GFAP+ and Notch+) or relatively active (GFAP+ and Notch-) in the salamander brain. Lindsey and colleagues highlight how, in zebrafish, heterogeneity of NSCs may correlate with varying capacities for brain growth, plasticity and regeneration. While active and quiescent radial glial like NSCs exist in fish as they do in mammals, a distinct type of NSC also exists in fish with neuroepithelial like properties. Through development, different brain regions contain biased proportions of different NSC subtypes with the potential to modulate the rates of neurogenesis in a region-specific manner in response to distinct sensory cues. Moreover, in response to injury there are differential responses of neuroepithelial like and radial glial like NSCs in distinct brain regions. Interestingly, an inflammatory niche may regulate reactive neurogenesis from quiescent radial glial like NSCs in zebrafish, reminiscent of the SVZ in mice. Some common themes have emerged from these reviews: (1) NSCs exist assubpopulations often with different molecular profiles, morphologies, proliferative characteristics and regenerative potentials; (2) in most instances, the lineage relationship of these distinct types of NSCs and the reasons for their biased distributions in the brain remain unresolved; (3) NSC niches dictate behavior of NSCs in a region-specific manner; (4) adaptations in the niche suggest that inflammation and reactive oxygen species, which are normally thought to limit regeneration, may actually promote neurogenesis in specific circumstances; (5) a common future goal is to use single cell transcriptomic approaches to resolve identities and lineages within neurogenic niches. Overall, this Special Issue identifies important areas of future research that will bring us closer to understanding the mechanistic basis of the development and maintenance of NSC heterogeneity that could be used to better manipulate specific human NSCs for therapeutic innovation. [no pdf