Mesenchymal Stem Cells as Promoters, Enhancers, and Playmakers of the Translational Regenerative Medicine.

Since their first isolation and characterization by Friedenstein et al. in 1974 [1], mesenchymal stem cells (MSCs) were proven essential for tissue regeneration and homeostasis

Accidental Politicians: How Randomly Selected Legislators Can Improve Parliament Efficiency

We study a prototypical model of a Parliament with two Parties or two Political Coalitions and we show how the introduction of a variable percentage of randomly selected independent legislators can increase the global efficiency of a Legislature, in terms of both the number of laws passed and the average social welfare obtained. We also analytically find an "efficiency golden rule" which allows to fix the optimal number of legislators to be selected at random after that regular elections have established the relative proportion of the two Parties or Coalitions. These results are in line with both the ancient Greek democratic system and the recent discovery that the adoption of random strategies can improve the efficiency of hierarchical organizations.Comment: 19 pages, 7 figures, new improved and longer versio

A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection.

BACKGROUND: Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. RESULTS: In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+) neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd/β-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH+ neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of β-catenin signaling within the SNpc. CONCLUSION: These results defining a novel Wnt1/Fzd-1/β-catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinson's disease.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Microglia Polarization, Gene-Environment Interactions and Wnt/β-Catenin Signaling: Emerging Roles of Glia-Neuron and Glia-Stem/Neuroprogenitor Crosstalk for Dopaminergic Neurorestoration in Aged Parkinsonian Brain.

Neuroinflammatory processes are recognized key contributory factors in Parkinson's disease (PD) physiopathology. While the causes responsible for the progressive loss of midbrain dopaminergic (mDA) neuronal cell bodies in the subtantia nigra pars compacta are poorly understood, aging, genetics, environmental toxicity, and particularly inflammation, represent prominent etiological factors in PD development. Especially, reactive astrocytes, microglial cells, and infiltrating monocyte-derived macrophages play dual beneficial/harmful effects, via a panel of pro- or anti-inflammatory cytokines, chemokines, neurotrophic and neurogenic transcription factors. Notably, with age, microglia may adopt a potent neurotoxic, pro-inflammatory "primed" (M1) phenotype when challenged with inflammatory or neurotoxic stimuli that hamper brain's own restorative potential and inhibit endogenous neurorepair mechanisms. In the last decade we have provided evidence for a major role of microglial crosstalk with astrocytes, mDA neurons and neural stem progenitor cells (NSCs) in the MPTP- (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-) mouse model of PD, and identified Wnt/β-catenin signaling, a pivotal morphogen for mDA neurodevelopment, neuroprotection, and neuroinflammatory modulation, as a critical actor in glia-neuron and glia-NSCs crosstalk. With age however, Wnt signaling and glia-NSC-neuron crosstalk become dysfunctional with harmful consequences for mDA neuron plasticity and repair. These findings are of importance given the deregulation of Wnt signaling in PD and the emerging link between most PD related genes, Wnt signaling and inflammation. Especially, in light of the expanding field of microRNAs and inflammatory PD-related genes as modulators of microglial-proinflammatory status, uncovering the complex molecular circuitry linking PD and neuroinflammation will permit the identification of new druggable targets for the cure of the disease. Here we summarize recent findings unveiling major microglial inflammatory and oxidative stress pathways converging in the regulation of Wnt/β-catenin signaling, and reciprocally, the ability of Wnt signaling pathways to modulate microglial activation in PD. Unraveling the key factors and conditons promoting the switch of the proinflammatory M1 microglia status into a neuroprotective and regenerative M2 phenotype will have important consequences for neuroimmune interactions and neuronal outcome under inflammatory and/or neurodegenerative conditions

Chronic obstructive pulmonary disease, a risk factor for SARS-CoV-2 morbidity and mortality?

Chronic obstructive pulmonary disease (COPD) is a major health problem difficult to treat due to underlying neutrophilic inflammation resistant to inhaled corticosteroids in most patients. Increased blood and sputum eosinophils are associated with more frequent exacerbation. Increased blood and sputum eosinophils are associated with more frequent exacerbation. Novel coronavirus SRAS-CoV-2 has infected humans in all age groups of all ethnicities.La enfermedad pulmonar obstructiva crónica (EPOC) es un problema de salud difícil de tratar debido a la inflamación neutrofílica subyacente que resiste a la terapia con corticosteroides inhalados. El aumento de eosinófilos en sangre y en el esputo cursa con frecuentes exacerbaciones. El nuevo coronavirus (SRAS-CoV-2) infecta a los humanos de todos los grupos etarios y étnicos