Reversal of Postnatal Brain Astrocytes and Ependymal Cells towards a Progenitor Phenotype in Culture.

Astrocytes and ependymal cells have been reported to be able to switch from a mature cell identity towards that of a neural stem/progenitor cell. Astrocytes are widely scattered in the brain where they exert multiple functions and are routinely targeted for in vitro and in vivo reprogramming. Ependymal cells serve more specialized functions, lining the ventricles and the central canal, and are multiciliated, epithelial-like cells that, in the spinal cord, act as bi-potent progenitors in response to injury.

Alpha-synuclein pathology in the "weaver" mouse, a genetic model of dopaminergic denervation.

Alpha-synuclein plays a pivotal role in Parkinson's disease (PD) pathogenesis, with α-synuclein aggregates/oligomers being identified as toxic species and phosphorylation at Serine 129 promoting aggregation/oligomerization. We investigated the biochemical profile of α-synuclein in the "weaver" mouse, a genetic PD model. Our results revealed increased Serine 129 phosphorylation in the midbrain, striatum, and cortex at a phase of established dopaminergic degeneration on postnatal day 100.

The "Brain Milking" Method for the Isolation of Neural Stem Cells and Oligodendrocyte Progenitor Cells from Live Rats.

Tissue-specific neural stem cells (NSCs) remain active in the mammalian postnatal brain. They reside in specialized niches, where they generate new neurons and glia. One such niche is the subependymal zone (SEZ; also called the ventricular-subventricular zone), which is located across the lateral walls of the lateral ventricles, adjacent to the ependymal cell layer.

Enhancement of endogenous midbrain neurogenesis by microneurotrophin BNN-20 after neural progenitor grafting in a mouse model of nigral degeneration.

We have previously shown the neuroprotective and pro-neurogenic activity of microneurotrophin BNN-20 in the substantia nigra of the “weaver” mouse, a model of progressive nigrostriatal degeneration. Here, we extended our investigation in two clinically-relevant ways. First, we assessed the effects of BNN-20 on human induced pluripotent stem cell-derived neural progenitor cells and neurons derived from healthy and parkinsonian donors.

Divergence between Neuronal and Oligodendroglial Cell Fate, in Postnatal Brain Neural Stem Cells, Leads to Divergent Properties in Polymorphic In Vitro Assays.

Two main stem cell pools exist in the postnatal mammalian brain that, although they share some "stemness" properties, also exhibit significant differences. Multipotent neural stem cells survive within specialized microenvironments, called niches, and they are vulnerable to ageing. Oligodendroglial lineage-restricted progenitor cells are widely distributed in the brain parenchyma and are more resistant to the effects of ageing.

Endogenous exogenous cell replacement for Parkinson's disease: where are we at and where are we going?

Parkinson's disease is the second most common neurodegenerative disease and has currently no effective treatment, one that would be able to stop or reverse the loss of dopaminergic neurons in the substantia nigra pars compacta. In addition, Parkinson's disease diagnosis is typically done when a significant percentage of the dopaminergic neurons is already lost. In neurodegenerative disorders, some therapeutic strategies could be effective only at inhibiting further degeneration; on the other hand, cell replacement therapies aim at replacing lost neurons, an approach that would be ideal for the treatment of Parkinson's disease.

Heterogeneity of quiescent and active neural stem cells in the postnatal brain.

In the postnatal mammalian brain, neurogenic activity is retained in anatomically restricted areas, driven by pools of Neural Stem Cells (NSCs). These cells and their progeny have been studied intensively as potential targets for regenerative treatments, aiming at either their manipulation or their use as sources of cells for transplantation-based strategies. Although their full identity, heterogeneity and differentiation potential remain elusive, due to the absence of specific cell-type markers, our knowledge of their properties is constantly expanding.

Isolation of neural stem and oligodendrocyte progenitor cells from the brain of live rats.

Postnatal brain neural stem and progenitor cells (NSPCs) cluster in anatomically inaccessible stem cell niches, such as the subependymal zone (SEZ). Here, we describe a method for the isolation of NSPCs from live animals, which we term "milking." The intracerebroventricular injection of a release cocktail, containing neuraminidase, integrin-β1-blocking antibody, and fibroblast growth factor 2, induces the controlled flow of NSPCs in the cerebrospinal fluid, where they are collected via liquid biopsies.

Characterization of substantia nigra neurogenesis in homeostasis and dopaminergic degeneration: beneficial effects of the microneurotrophin BNN-20.

Background: Loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) underlines much of the pathology of Parkinson's disease (PD), but the existence of an endogenous neurogenic system that could be targeted as a therapeutic strategy has been controversial. BNN-20 is a synthetic, BDNF-mimicking, microneurotrophin that we previously showed to exhibit a pleiotropic neuroprotective effect on the dopaminergic neurons of the SNpc in the "weaver" mouse model of PD. Here, we assessed its potential effects on neurogenesis.

Being a Neural Stem Cell: A Matter of Character But Defined by the Microenvironment.

The cells that build the nervous system, either this is a small network of ganglia or a complicated primate brain, are called neural stem and progenitor cells. Even though the very primitive and the very recent neural stem cells (NSCs) share common basic characteristics that are hard-wired within their character, such as the expression of transcription factors of the SoxB family, their capacity to give rise to extremely different neural tissues depends significantly on instructions from the microenvironment. In this chapter we explore the nature of the NSC microenvironment, looking through evolution, embryonic development, maturity and even disease.

Subependymal Zone-Derived Oligodendroblasts Respond to Focal Demyelination but Fail to Generate Myelin in Young and Aged Mice.

Two populations of oligodendrogenic progenitors co-exist within the corpus callosum (CC) of the adult mouse. Local, parenchymal oligodendrocyte progenitor cells (pOPCs) and progenitors generated in the subependymal zone (SEZ) cytogenic niche. pOPCs are committed perinatally and retain their numbers through self-renewing divisions, while SEZ-derived cells are relatively "young," being constantly born from neural stem cells.

How Necessary is the Vasculature in the Life of Neural Stem and Progenitor Cells? Evidence from Evolution, Development and the Adult Nervous System.

Augmenting evidence suggests that such is the functional dependance of neural stem cells (NSCs) on the vasculature that they normally reside in "perivascular niches". Two examples are the "neurovascular" and the "oligovascular" niches of the adult brain, which comprise specialized microenvironments where NSCs or oligodendrocyte progenitor cells survive and remain mitotically active in close proximity to blood vessels (BVs). The often observed co-ordination of angiogenesis and neurogenesis led to these processes being described as "coupled".

Oligodendrocyte progenitor cells: the ever mitotic cells of the CNS.

Oligodendrocyte Progenitor Cells (OPCs) first appear at mid embryogenic stages during development of the mammalian CNS and a mitotically active population of them remains present even into late adulthood. During the life-time of the organism they initially proliferate and migrate in order to populate the whole nervous tissue, then they massively generate oligodendrocytesand finally they switch to a less mitotically active phase generating new oligodendrocytes at a slow rate in the adult brain; importantly, they can regenerate acutely or chronically destroyed myelin. All the above depend on the capacity of OPCs to regulate their cell cycle within different contexts.

Disc1 variation leads to specific alterations in adult neurogenesis.

Disrupted in schizophrenia 1 (DISC1) is a risk factor for a spectrum of neuropsychiatric illnesses including schizophrenia, bipolar disorder, and major depressive disorder. Here we use two missense Disc1 mouse mutants, described previously with distinct behavioural phenotypes, to demonstrate that Disc1 variation exerts differing effects on the formation of newly generated neurons in the adult hippocampus. Disc1 mice carrying a homozygous Q31L mutation, and displaying depressive-like phenotypes, have fewer proliferating cells while Disc1 mice with a homozygous L100P mutation that induces schizophrenia-like phenotypes, show changes in the generation, placement and maturation of newly generated neurons in the hippocampal dentate gyrus.

The late response of rat subependymal zone stem and progenitor cells to stroke is restricted to directly affected areas of their niche.

Ischaemia leads to increased proliferation of progenitors in the subependymal zone (SEZ) neurogenic niche of the adult brain and to generation and migration of newborn neurons. Here we investigated the spatiotemporal characteristics of the mitotic activity of adult neural stem and progenitor cells in the SEZ during the sub-acute and chronic post-ischaemic phases. Ischaemia was induced by performing a 1h unilateral middle cerebral artery occlusion (MCAO) and tissue was collected 4/5 weeks and 1 year after the insult.

Neurogenesis in the adult mammalian brain: how much do we need, how much do we have?

The last two decades cytogenic processes (both neurogenic and gliogenic) driven by neural stem cells surviving within the adult mammalian brain have been extensively investigated. It is now well established that within at least two cytogenic niches, the subependymal zone of the lateral ventricles and the subgranular zone in the dentate gyrus, new neurons are born everyday with a fraction of them being finally incorporated into established neuronal networks in the olfactory bulb and the hippocampus, respectively. But how significant is adult neurogenesis in the context of the mature brain and what are the possibilities that these niches can contribute significantly in tissue repair after degenerative insults, or in the restoration of normal hippocampal function in the context of mental and cognitive disorders? Here, we summarise the available data on the normal behaviour of adult neural stem cells in the young and the aged brain and on their response to degeneration.

Reforming the Greek health system: a role for non-medical, clinical bioscientists.

Within the context of the recent debt crisis and the subsequently adopted austerity measures, the Greek health system faces important challenges including the necessity to rationalize public spending. One domain where there is scope for reducing expenses is laboratory medicine services, that are provided by both public and private facilities. Specialized non-medical, clinical bioscientists (such as molecular biologists, biochemists and geneticists) massively participate in the provision of laboratory medicine services in both sectors; however, they are excluded from key positions, such as the direction of laboratories and sitting in regulatory bodies.

Extracellular matrix and the neural stem cell niche.

Basal lamina is present in many stem cell niches, but we still have a poor understanding of the role of this and other extracellular matrix (ECM) components. Here, we review current knowledge regarding ECM expression and function in the neural stem cell niche, focusing on the subependymal zone of the adult CNS. An increasing complexity of ECM molecules has been described, and a number of receptors expressed on the stem cells identified.

The number of stem cells in the subependymal zone of the adult rodent brain is correlated with the number of ependymal cells and not with the volume of the niche.

The mammalian subependymal zone (SEZ; often called subventricular) situated at the lateral walls of the lateral ventricles of the brain contains a pool of relatively quiescent adult neural stem cells whose neurogenic activity persists throughout life. These stem cells are positioned in close proximity both to the ependymal cells that provide the cerebrospinal fluid interface and to the blood vessel endothelial cells, but the relative contribution of these 2 cell types to stem cell regulation remains undetermined. Here, we address this question by analyzing a naturally occurring example of volumetric scaling of the SEZ in a comparison of the mouse SEZ with the larger rat SEZ.

Can adult neural stem cells create new brains? Plasticity in the adult mammalian neurogenic niches: realities and expectations in the era of regenerative biology.

Since the first experimental reports showing the persistence of neurogenic activity in the adult mammalian brain, this field of neurosciences has expanded significantly. It is now widely accepted that neural stem and precursor cells survive during adulthood and are able to respond to various endogenous and exogenous cues by altering their proliferation and differentiation activity. Nevertheless, the pathway to therapeutic applications still seems to be long.

Quiescence and activation of stem and precursor cell populations in the subependymal zone of the mammalian brain are associated with distinct cellular and extracellular matrix signals.

The subependymal zone (SEZ) of the lateral ventricles is one of the areas of the adult brain where new neurons are continuously generated from neural stem cells (NSCs), via rapidly dividing precursors. This neurogenic niche is a complex cellular and extracellular microenvironment, highly vascularized compared to non-neurogenic periventricular areas, within which NSCs and precursors exhibit distinct behavior. Here, we investigate the possible mechanisms by which extracellular matrix molecules and their receptors might regulate this differential behavior.