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Compelling evidence exists that non-haematopoietic stem cells, including mesenchymal (MSCs) and neural/progenitor stem cells (NPCs), exert a substantial beneficial and therapeutic effect after transplantation in experimental central nervous system (CNS) disease models through the secretion of immune modulatory or neurotrophic paracrine factors.This paracrine hypothesis has inspired an alternative outlook on the use of stem cells in regenerative neurology. In this paradigm, significant repair of the injured brain may be achieved by injecting the biologics secreted by stem cells (secretome), rather than implanting stem cells themselves for direct cell replacement. The stem cell secretome (SCS) includes cytokines, chemokines and growth factors, and has gained increasing attention in recent years because of its multiple implications for the repair, restoration or regeneration of injured tissues.Thanks to recent improvements in SCS profiling and manipulation, investigators are now inspired to harness the SCS as a novel alternative therapeutic option that might ensure more efficient outcomes than current stem cell-based therapies for CNS repair.This review discusses the most recent identification of MSC- and NPC-secreted factors, including those that are trafficked within extracellular membrane vesicles (EVs), and reflects on their potential effects on brain repair. It also examines some of the most convincing advances in molecular profiling that have enabled mapping of the SCS.

The idea that stem cell therapies work only via cell replacement is challenged by the observation of consistent intercellular molecule exchange between the graft and the host. Here we defined a mechanism of cellular signaling by which neural stem/precursor cells (NPCs) communicate with the microenvironment via extracellular vesicles (EVs), and we elucidated its molecular signature and function. We observed cytokine-regulated pathways that sort proteins and mRNAs into EVs. We described induction of interferon gamma (IFN-γ) pathway in NPCs exposed to proinflammatory cytokines that is mirrored in EVs. We showed that IFN-γ bound to EVs through Ifngr1 activates Stat1 in target cells. Finally, we demonstrated that endogenous Stat1 and Ifngr1 in target cells are indispensable to sustain the activation of Stat1 signaling by EV-associated IFN-γ/Ifngr1 complexes. Our study identifies a mechanism of cellular signaling regulated by EV-associated IFN-γ/Ifngr1 complexes, which grafted stem cells may use to communicate with the host immune system.

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We investigated the structural effects induced by Al3+ on different beta-amyloid (Abeta) fragments at pH 7.4 and T=25 degrees C, with particular attention given to the sequences 1-40 and 1-42. Al3+ caused peptide enrichment in beta sheet structure and formation of solvent-exposed hydrophobic clusters. These intermediates evolved to polymeric aggregates which organized in fibrillar forms in the case of the Al3+-Abeta(1-42) complex. Comparative studies showed that Zn2+ and Cu2+ were much less efficient than Al3+ in stimulating the spontaneous aggregation/fibrillogenesis of Abetas. Studies with liposomes as membrane models showed dramatic changes in the structural properties of the lipid bilayer in the presence of Al3+-Abeta complexes, suggesting a major role of Al3+ in Abeta-induced cell dysfunction. Al3+ effects were abolished by desferrioxamine mesylate (DFO) only in solution. We concluded that, in vivo, DFO may act as a protective agent by preventing or reverting Abeta aggregation in the extracellular spaces.

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Neurodegeneration is a complex and multifaceted process leading to many chronic diseased states. Neurodegenerative disorders include a number of different pathological conditions, like Alzheimer's and Parkinson's diseases, which share similar critical metabolic processes, such as protein aggregation, which could be affected by some metal ions. A huge number of reports indicate that, among putative aggravating factors, metal ions (Al, Zn, Cu, Fe) could specifically impair protein aggregation of Abeta, prion protein, ataxin, huntingtin, etc. and their oligomeric toxicity. While studying the molecular basis of these diseases, it has become clear that protein conformation plays a critical role in the pathogenic process. In this review, we will focus on Alzheimer's disease and on the role of metal ions, specifically aluminium, in affecting amyloid aggregation, oligomerization and toxicity.

Mounting evidence suggests a central role for transition biometals in the etiopathogenesis of neurodegenerative diseases (ND). Indeed, while studying the molecular basis for this heterogeneous group of diseases, it has become increasingly evident that biometals and nonphysiological Al are often involved in pathology onset and progression, either by affecting the conformation of specific proteins or by exacerbating local oxidative stress. The apparently critical role played by metal dishomeostasis in ND makes chelation therapy an attractive pharmacological option. However, classical metal chelation approaches, relying on potent metal ligands, turned out to be successful only in those rare cases where exceptional brain metal accumulation occurs due to specific defects in metal metabolism. In contrast, metal-targeted approaches using ligand of intermediate strength seem to be more appropriate in fighting the major ND, although their benefits are still questioned. We report here a survey of recent evidences supporting the use of a variety of metal ligands, and even functionalized nanoparticles, for the treatment of the most common ND. The beneficial neuropharmacological actions of metal-targeted agents most likely arise from local metal redistribution rather than from massive metal removal. The perspectives for the development of new effective agents against ND are critically discussed.