1,721,005 research outputs found
Editorial: Crosstalk between the Osteogenic and Neurogenic Stem Cell Niches: How Far are They from Each Other?
Full text linkDespite the intense research on adult neural stem cell biology suggested possible translational outcomes in regenerative medicine for neurodegenerative diseases, neuroregeneration is unlikely to occur in adult brain, due to intrinsic features that characterize the neural stem cell niche.
Mesenchymal stem cells (MSCs), osteogenic stem cells residing in the bone marrow stroma (also named bone marrow stromal cells), have been long considered highly plastic multipotent precursors, able to commit toward diversified lineages, including non-mesodermal ones. Their in vitro plasticity and ease of processing prompted their wide, sometimes untimely, exploitation in diversified regenerative medicine applications (Park et al., 2012; Bianco et al., 2013). They have been tested also for their putative, yet widely debated, neuroregenerative potential. This controversial issue stimulated this Research Topic, which aims to delve into relevant scientific milestones addressing the differences, possible interconnections, and overlaps between the osteogenic and the neurogenic niches' biology.
The debated neuronal transdifferentiation potential of MSCs recently led to their inappropriate exploitation for the treatment of neurodegenerative disorders. The regulatory and ethical issues regarding this topic have been discussed in the Opinion paper by Solarino et al., delving into a recent Italian case of medical malpractice, which triggered significant international dispute (Abbott, 2013; Blasimme and Rial-Sebbag, 2013). Indeed, a better clarification of the specific features displayed by the osteogenic and the neurogenic stem cell niches is needed, as discussed by Lattanzi et al. This mini-review provides a pairwise comparison of the two niches within their in vivo environments, highlighting functionally relevant similarities and differences that should be considered to achieve a more rational clinical translation.
The contribution by Salgado et al. provides an exhaustive description of osteogenic and neural stem cells' features, focusing on their possible interaction within the brain environment. In particular, the MSCs' secretome is known to exert autocrine and paracrine effects that may be relevant for potential therapeutic exploitations, also in the central nervous system (Ribeiro et al., 2011; Drago et al., 2013; Kim et al., 2013; Sart et al., 2014; Wright et al., 2014).
The role of neural crest stem cells (NCSCs) in regulating the bone marrow niche is provided in the review by Coste et al. NCSCs are capable of epithelial-to-mesenchymal transition, and ultimately give rise to both neural precursors and nestin-positive MSCs, actively involved in the homeostatic regulation of the hematopoietic stem cell niche (Achilleos and Trainor, 2012; Mayor and Theveneau, 2013).
A significant overlap between the two niches relies on the molecular (Wnt, NOTCH, FGF, TGF-BMP, SHH signaling pathways) and secretome (BDNF, NGF, VEGF, PDGF) profiles, along with the intimate relationship with vessels, being a common structural feature observed in adult stem cell niches.
Diverse phylogenetically old signaling pathways, including nucleotides and neuropeptides, are shared between the osteogenic and the neurogenic niches, exerting trophic, and immunomodulatory functions. Cavaliere et al. exhaustively discussed the often opposing roles played by purinergic ligands. These establish a common paracrine pathway that modulates MSCs' and NSCs' activity, in both physiological and pathological conditions. They appear to be involved in the crosstalk between the two niches, by modulating the immune response, which triggers stem cell recruitment after stressful insults (Cavaliere et al.).
Among neuropeptides, the direct effects of neuropeptide Y (NPY), mediator for signaling in both neurogenic and osteogenic niches, has been reviewed by Geloso et al., with special attention to its effects on neurogenic niche. Data indicating a direct pro-neurogenic effect of NPY on NSCs, as well as the concomitant modulatory action on astrocytes, microglia, and endothelium activities within the niche have been discussed. Interestingly, a possible crosstalk between released nucleotides and NPY related pathways emerges (Jia and Hegg, 2012), suggesting that they could also represent a point of intersection between shared ancient molecular pathways.
Neurotransmitters released by the sympathetic nervous system, interestingly including NPY, as recently reviewed by Park et al. (2015), are known to be also involved in the regulation of hematopoietic stem cell (HSC) functions, mainly acting on endothelial cells and nestin-positive MSCs, which retain HSCs. In this regard, the relevance of catecholaminergic modulation of hematopoiesis has been extensively reviewed by Cosentino and coworkers (Cosentino et al.), highlighting their established role in the complex network of neural and neuroendocrine agents that regulate stem cell biology (Cosentino et al.).
Within the wide range of external stimuli acting on the epigenetic control of adult tissue stem cell niches, the effects of extremely-low frequency electromagnetic field (ELFEF) stimulation is emerging as a tool to modulate neurogenic and osteogenic processes, as discussed by Leone et al. They highlighted the possible shared pathways induced by ELFEFS on both niches, including Wnt/beta-catenin signaling and the activation of p300 or other histone acetyltransferases by Runx2 (Leone et al.).
The interdependence of brain and skull during development seems to rely also on the role of interposed meninges (Richtsmeier and Flaherty, 2013). Within this intriguing topic, Bifari et al. provided findings showing the distribution of neural precursor markers in rat meninges during development up to adulthood, related to the newly identified niche function of meninges (Decimo et al., 2011).
Finally, an interesting evolutionary perspective on the relation between osteogenesis and neurogenesis is provided in the opinion paper by Boeckx and Benítez-Burraco, who approached this topic from a different “biolinguistic” standpoint. The Authors postulated that critical genes active in the osteogenic niche (including homeogenes, e.g. DLXs, morphogens, e.g. BMPs, and the master regulatory RUNX2 gene), hence giving rise to skull globularity in anatomically modern humans, also have important consequences in brain development and plasticity, ultimately leading to our distinctive mode of cognition (Boeckx and Benítez-Burraco).
Taken together, the papers included in this research topic seem to suggest an emerging cross-domain scenario in which significant molecular signaling and biological features are shared between osteogenic and neurogenic stem cells niches. The two niches appear to be interconnected in evolution, during development, and further beyond. Nonetheless, relevant differences in the relative stem cell niche dynamics should not be neglected, in order to appropriately design potential cross-lineage tissue regenerative strategies
gamma-Aminobutyric acidergic interneuron vulnerability to aging in canine prefrontal cortex.
No full textThe aged dog is considered a promising model for examining molecular and cellular processes involved in a variety of human neurological disorders. By using the canine counterpart of senile dementia of the Alzheimer's type (ccSDAT), we investigated the specific vulnerability of the gamma-aminobutyric acid (GABA) cortical subset of interneurons, characterized by their calcium-binding protein content, to neuronal death. Dogs representing a large variety of breeds were classified into three groups: young control, aged control, and ccSDAT. In all dogs, the general distribution and cell typology of parvalbumin-, calretinin-, and calbindin-positive neurons were found to be similar to those in the human. As in Alzheimer's disease patients, neurons displaying parvalbumin or calretinin immunoreactivity were resistant and the calbindin-positive ones depleted. Together with aging, amyloid deposition in its early phase (stage II) participates in this specific neuronal death, but with a lower potency. In conclusion, our data provide evidence that preservation of GABAergic cortical interneurons has to be focused on the early stage of beta-amyloid deposition. We also demonstrate the usefulness of dogs of all breeds for investigating the early phases of human brain aging and Alzheimer's disease
Neuroprotective Strategies in Hippocampal Neurodegeneration induced by the Neurotoxicant Trimethyltin. Neurochemical Research
No full textThe selective vulnerability of specific neuronal subpopulations to trimethyltin (TMT), an organotin compound with neurotoxicant effects selectively involving the limbic system and especially marked in the hippocampus, makes it useful to obtain in vivo models of neurodegeneration associated with behavioural alterations, such as hyperactivity and aggression, cognitive impairment as well as temporal lobe epilepsy. TMT has been widely used to study neuronal and glial factors involved in selective neuronal death, as well as the molecular mechanisms leading to hippocampal neurodegeneration (including neuroinflammation, excitotoxicity, intracellular calcium overload, mitochondrial dysfunction and oxidative stress). It also offers a valuable instrument to study the cell-cell interactions and signalling pathways that modulate injury-induced neurogenesis, including the involvement of newly generated neurons in the possible repair processes. Since TMT appears to be a useful tool to damage the brain and study the various responses to damage, this review summarises current data from in vivo and in vitro studies on neuroprotective strategies to counteract TMT-induced neuronal death, that may be useful to elucidate the role of putative candidates for translational medical research on neurodegenerative diseases
Expression of CD44 and Its Spliced Variants: Innate and Inducible Roles in Nervous Tissue Cells and Their Environment
No full textCD44, a structurally diverse cell-surface glycoprotein, plays a multifaceted and indispensable role in neural tissue across both physiological and pathological conditions. It orchestrates complex cell–extracellular matrix interactions and intracellular signaling through its variant isoforms and post-translational modifications and is broadly expressed in neural stem/progenitor cells, microglia, astrocytes, and selected neuronal populations. The interactions of CD44 with ligands such as hyaluronan and osteopontin regulate critical cellular functions, including migration, differentiation, inflammation, and synaptic plasticity. In microglia and macrophages, CD44 mediates immune signaling and phagocytic activity, and it is dynamically upregulated in neuroinflammatory diseases, particularly through pathways involving Toll-like receptor 4. CD44 expression in astrocytes is abundant during central nervous system development and in diseases, contributing to glial differentiation, reactive astrogliosis, and scar formation. Though its expression is less prominent in mature neurons, CD44 supports neural plasticity, circuit organization, and injury-induced repair mechanisms. Additionally, its expression at nervous system barriers, such as the blood–brain barrier, underscores its role in regulating vascular permeability during inflammation and ischemia. Collectively, CD44 emerges as a critical integrator of neural cell function and intercellular communication. Although the roles of CD44 in glial cells appear to be similar to those explored in other tissues, the expression of this molecule and its variants on neurons reveals peculiar functions. Elucidating the cell-type-specific roles and regulation of CD44 variants may offer novel therapeutic strategies for diverse neurological disorders
" Trimethyltin-Induced Hippocampal Degeneration As A Tool To Investigate Neurodegenerative Processes"
No full textTrimethyltin (TMT), an organotin compound with neurotoxicant effects selectively localised in the limbic system and especially marked in the hippocampus, is considered a useful tool to obtain an experimental model of neurodegeneration. Animals exposed to TMT develop behavioural alterations (hyperactivity, aggression), cognitive impairment (memory loss and learning impairment) and spontaneous seizures. TMT induces selective neuronal death involving the granular neurons of the Fascia Dentata and the pyramidal cells of the Cornu Ammonis, with a different pattern of severity and extension according to the various species studied and the dosage schedule. TMT-induced neurodegenerative events are associated with the activation of astrocytes and microglial cells and with the upregulation of proinflammatory cytokines. While the mechanisms by which TMT induces neurodegeneration are still not understood, many hypotheses seem to suggest that neuronal damage could be largely dependent on calcium overload. This review summarizes current data from in vivo and in vitro studies of the neurotoxic effects of TMT, focusing on the hypotheses regarding the mechanisms leading to neuronal death induced by the toxin
Effect of acetyl-L-carnitine on hyperactivity and spatial memory deficits of rats exposed to neonatal anoxia
No full textThe effect of acetyl-l-carnitine (ALC) on behavioral deficits following neonatal anoxia (N2 100% for 25 min at 30 h after birth) was
studied in the rat. Transient hyperactivity at P20–P45 postnatal days and permanent spatial memory deficits were shown by anoxic rats.
A chronic ALC treatment (50 mg/kg per die injected intraperitoneally from P2, after anoxia, to P60) significantly reduced the transient
increase in sniffing, rearing and locomotory activity of anoxic rats, but, mostly, ameliorated the spatial memory performances in a maze
at P30–P40 and in a water maze at P50–P60. No behavioral changes were seen in ALC-treated animals that received sham-exposure at
birth. On the basis of these results, the use of ALC for the treatment of perinatal asphyctic insults in children is suggeste
Development of GABA and calcium binding proteins immunoreactivity in the rat hippocampus following neonatal anoxia
No full textThe consequences of neonatal anoxia (N2 100% for 25 min at 30 h after birth) on the rat hippocampus were studied 7-60 days postnatally with immunocytochemistry for gamma-aminobutyric acid (GABA), parvalbumin (PV) and calbindin-D28k (CB). In both sham-treated
and anoxic rats, GABA imlmunoreactivity presented a mature expression since early stages, while PV and CB immunoreactivity showed
a major postnatal development. In anoxic animals, a significant reduction in the number of hippocampal GABAimmunoreactive neurons
was observed at all tilme-points analysed, a transitory effect on PV immunoreactivity was seen at P7 and P21, while no modifications
in the number of CEI-immunoreactive neurons could be found. Thus, selective vulnerability of GABA-containing neurons and
relative resistance of neurons in which PV or CB immunoreactivity is present or is expressed later, occur in the hippocampus after neonatal
anoxia. The role of calcium binding proteins (CBP) in nerve cell protection is discussed
Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models
Full text linkMicroglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or "pruning") of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients' long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models
Cyclooxygenase-2 and caspase 3 expression in trimethyltin-induced apoptosis in the mouse hippocampus
No full textThe neurotoxicant trimethyltin (TMT) induces massive neuronal loss in vivo in the hippocampus of rodents, accompanied by behavioral alterations. The present study investigates the pattern of cell death after in vivo administration of TMT to adult mice. In the granular cell layer of the Dentate Gyrus, TUNEL staining detected DNA fragmentation, and apoptotic bodies were also evident. In addition, a ladder pattern of internucleosomal DNA fragmentation was shown in agarose gel electrophoresis. We show that activated caspase-3, which is known to play a pivotal role in apoptotic processes, is clearly expressed by degenerating neurons. Inducible cyclooxygenase is also expressed at cytoplasmic level by degenerating granular neurons, suggesting that this enzyme may participate in TMT-induced neurodegeneration
The S100B protein in biological fluids: more than a lifelong biomarker of brain distress
No full textS100B is a calcium-binding protein concentrated in glial cells, although it has also been detected in definite extra-neural cell types. Its biological role is still debated. When secreted, S100B is believed to have paracrine/autocrine trophic effects at physiological concentrations, but toxic effects at higher concentrations. Elevated S100B levels in biological fluids (CSF, blood, urine, saliva, amniotic fluid) are thus regarded as a biomarker of pathological conditions, including perinatal brain distress, acute brain injury, brain tumors, neuroinflammatory/neurodegenerative disorders, psychiatric disorders. In the majority of these conditions, high S100B levels offer an indicator of cell damage when standard diagnostic procedures are still silent. The key question remains as to whether S100B is merely leaked from injured cells or is released in concomitance with both physiological and pathological conditions, participating at high concentrations in the events leading to cell injury. In this respect, S100B levels in biological fluids have been shown to increase in physiological conditions characterized by stressful physical and mental activity, suggesting that it may be physiologically regulated and raised during conditions of stress, with a putatively active role. This possibility makes this protein a candidate not only for a biomarker but also for a potential therapeutic target
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