84 results on '"Luca Peruzzotti-Jametti"'
Search Results
2. Time-resolved single-cell RNAseq profiling identifies a novel Fabp5+ subpopulation of inflammatory myeloid cells with delayed cytotoxic profile in chronic spinal cord injury
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Regan Hamel, Luca Peruzzotti-Jametti, Katherine Ridley, Veronica Testa, Bryan Yu, David Rowitch, John C. Marioni, and Stefano Pluchino
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Single cell RNA sequencing ,Neuroinflammation ,Fatty acid binding protein 5 ,Spinal cord injury ,Fate-mapping myeloid cells ,Myeloid cells ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Traumatic spinal cord injuries (SCI) are a group of highly debilitating pathologies affecting thousands annually, and adversely affecting quality of life. Currently, no fully restorative therapies exist, and SCI still results in significant personal, societal and financial burdens. Inflammation plays a major role in the evolution of SCI, with myeloid cells, including bone marrow derived macrophages (BMDMs) and microglia (MG) being primary drivers of both early secondary pathogenesis and delayed wound healing events.The precise role of myeloid cell subsets is unclear as upon crossing the blood-spinal cord barrier, infiltrating bone marrow derived macrophages (BMDMs) may take on the morphology of resident microglia, and upregulate canonical microglia markers, thus making the two populations difficult to distinguish.Here, we used time-resolved scRNAseq and transgenic fate-mapping to chart the transcriptional profiles of tissue-resident and -infiltrating myeloid cells in a mouse model of thoracic contusion SCI.Our work identifies a novel subpopulation of foam cell-like inflammatory myeloid cells with increased expression of Fatty Acid Binding Protein 5 (Fabp5) and comprise both tissue-resident and -infiltrating cells. Fabp5+ inflammatory myeloid cells display a delayed cytotoxic profile that is predominant at the lesion epicentre and extends into the chronic phase of SCI.
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- 2023
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3. Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke
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Amin Mottahedin, Hiran A. Prag, Andreas Dannhorn, Richard Mair, Christina Schmidt, Ming Yang, Annabel Sorby-Adams, Jordan J. Lee, Nils Burger, Duvaraka Kulaveerasingam, Margaret M. Huang, Stefano Pluchino, Luca Peruzzotti-Jametti, Richard Goodwin, Christian Frezza, Michael P. Murphy, and Thomas Krieg
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Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.
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- 2023
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4. Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73
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Lorna B. Jarvis, Daniel B. Rainbow, Valerie Coppard, Sarah K. Howlett, Zoya Georgieva, Jessica L. Davies, Harpreet Kaur Mullay, Joanna Hester, Tom Ashmore, Aletta Van Den Bosch, James T. Grist, Alasdair J. Coles, Hani S. Mousa, Stefano Pluchino, Krishnaa T. Mahbubani, Julian L. Griffin, Kourosh Saeb-Parsy, Fadi Issa, Luca Peruzzotti-Jametti, Linda S. Wicker, and Joanne L. Jones
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Biology (General) ,QH301-705.5 - Abstract
Jarvis et al demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A)-driven acquisition of CD73 expression, which along with CD39, enables expanded Tregs to convert ATP to immunosuppressive adenosine. Given this, the data suggests that Treg expansion protocols should be optimised for CD39/CD73 co-expression to enhance therapeutic potential.
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- 2021
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5. SUMOtherapeutics for Ischemic Stroke
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Paramesh Karandikar, Jakob V. E. Gerstl, Ari D. Kappel, Sae-Yeon Won, Daniel Dubinski, Monica Emili Garcia-Segura, Florian A. Gessler, Alfred Pokmeng See, Luca Peruzzotti-Jametti, and Joshua D. Bernstock
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stroke ,ischemia ,neuroprotection ,SUMOylation ,experimental therapeutics ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.
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- 2023
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6. Editorial: Hot Topics in Cellular Neuropathology
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Dirk M. Hermann, Aurel Popa-Wagner, Luca Peruzzotti-Jametti, and Matthias Gunzer
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neurodegeneration ,neuroinflammation ,microglia ,cognitive deficits ,dementia ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2022
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7. Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits
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Genevieve M. Sullivan, Andrew K. Knutsen, Luca Peruzzotti-Jametti, Alexandru Korotcov, Asamoah Bosomtwi, Bernard J. Dardzinski, Joshua D. Bernstock, Sandra Rizzi, Frank Edenhofer, Stefano Pluchino, and Regina C. Armstrong
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Neural stem cells ,Remyelination ,Cuprizone ,Multiple sclerosis ,Stem cell therapeutics ,Diffusion tensor imaging ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Multiple Sclerosis (MS) causes neurologic disability due to inflammation, demyelination, and neurodegeneration. Immunosuppressive treatments can modify the disease course but do not effectively promote remyelination or prevent long term neurodegeneration. As a novel approach to mitigate chronic stage pathology, we tested transplantation of mouse induced neural stem cells (iNSCs) into the chronically demyelinated corpus callosum (CC) in adult mice. Male C57BL/6 mice fed 0.3% cuprizone for 12 weeks exhibited CC atrophy with chronic demyelination, astrogliosis, and microglial activation. Syngeneic iNSCs were transplanted into the CC after ending cuprizone and perfused for neuropathology 2 weeks later. Magnetic resonance imaging (MRI) sequences for magnetization transfer ratio (MTR), diffusion-weighted imaging (T2), and diffusion tensor imaging (DTI) quantified CC pathology in live mice before and after iNSC transplantation. Each MRI technique detected progressive CC pathology. Mice that received iNSCs had normalized DTI radial diffusivity, and reduced astrogliosis post-imaging. A motor skill task that engages the CC is Miss-step wheel running, which demonstrated functional deficits from cuprizone demyelination. Transplantation of iNSCs resulted in marked recovery of running velocity. Neuropathology after wheel running showed that iNSC grafts significantly increased host oligodendrocytes and proliferating oligodendrocyte progenitors, while modulating axon damage. Transplanted iNSCs differentiated along astrocyte and oligodendrocyte lineages, without myelinating, and many remained neural stem cells. Our findings demonstrate the applicability of neuroimaging and functional assessments for pre-clinical interventional trials during chronic demyelination and detect improved function from iNSC transplantation. Directly reprogramming fibroblasts into iNSCs facilitates the future translation towards exogenous autologous cell therapies.
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- 2020
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8. Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients
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Kimberley Allen-Philbey, Stefania De Trane, Zhifeng Mao, Cesar Álvarez-González, Joela Mathews, Amy MacDougall, Andrea Stennett, Xia Zhou, Ozlem Yildiz, Ashok Adams, Lucia Bianchi, Camilla Blain, Christine Chapman, Karen Chung, Cris S Constantinescu, Catherine Dalton, Rachel A Farrell, Leonora Fisniku, Helen Ford, Bruno Gran, Jeremy Hobart, Zhaleh Khaleeli, Miriam Mattoscio, Sue Pavitt, Owen Pearson, Luca Peruzzotti-Jametti, Antonio Scalfari, Basil Sharrack, Eli Silber, Emma C Tallantyre, Stewart Webb, Benjamin P Turner, Monica Marta, Sharmilee Gnanapavan, Gunnar Juliusson, Gavin Giovannoni, David Baker, and Klaus Schmierer
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak ® ) in multiple sclerosis (MS) patients. Methods: Litak ® was offered to MS-patients irrespective of disease course. Litak ® 10 mg was administered for 3–4 days during week 1. Based on lymphocyte count at week 4, patients received another 0–3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17–72) years and EDSS 0–8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data ( n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data ( n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. Conclusions: Litak ® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.
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- 2021
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9. Stem Cell Therapies for Progressive Multiple Sclerosis
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Jayden A. Smith, Alexandra M. Nicaise, Rosana-Bristena Ionescu, Regan Hamel, Luca Peruzzotti-Jametti, and Stefano Pluchino
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progressive multiple sclerosis ,neural stem cell ,regenerative neuroimmunology ,mesenchymal stem cell ,stem cell therapy ,clinical trial ,Biology (General) ,QH301-705.5 - Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal degeneration. MS patients typically present with a relapsing-remitting (RR) disease course, manifesting as sporadic attacks of neurological symptoms including ataxia, fatigue, and sensory impairment. While there are several effective disease-modifying therapies able to address the inflammatory relapses associated with RRMS, most patients will inevitably advance to a progressive disease course marked by a gradual and irreversible accrual of disabilities. Therapeutic intervention in progressive MS (PMS) suffers from a lack of well-characterized biological targets and, hence, a dearth of successful drugs. The few medications approved for the treatment of PMS are typically limited in their efficacy to active forms of the disease, have little impact on slowing degeneration, and fail to promote repair. In looking to address these unmet needs, the multifactorial therapeutic benefits of stem cell therapies are particularly compelling. Ostensibly providing neurotrophic support, immunomodulation and cell replacement, stem cell transplantation holds substantial promise in combatting the complex pathology of chronic neuroinflammation. Herein, we explore the current state of preclinical and clinical evidence supporting the use of stem cells in treating PMS and we discuss prospective hurdles impeding their translation into revolutionary regenerative medicines.
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- 2021
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10. Metabolic Control of Smoldering Neuroinflammation
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Luca Peruzzotti-Jametti, Cory M. Willis, Regan Hamel, Grzegorz Krzak, and Stefano Pluchino
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microglia ,macrophages ,metabolism ,immunometabolism ,mitochondria ,smoldering inflammation ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Compelling evidence exists that patients with chronic neurological conditions, which includes progressive multiple sclerosis, display pathological changes in neural metabolism and mitochondrial function. However, it is unknown if a similar degree of metabolic dysfunction occurs also in non-neural cells in the central nervous system. Specifically, it remains to be clarified (i) the full extent of metabolic changes in tissue-resident microglia and infiltrating macrophages after prolonged neuroinflammation (e.g., at the level of chronic active lesions), and (ii) whether these alterations underlie a unique pathogenic phenotype that is amenable for therapeutic targeting. Herein, we discuss how cell metabolism and mitochondrial function govern the function of chronic active microglia and macrophages brain infiltrates and identify new metabolic targets for therapeutic approaches aimed at reducing smoldering neuroinflammation.
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- 2021
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11. SUMOylation promotes survival and integration of neural stem cell grafts in ischemic strokeResearch in context
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Joshua D. Bernstock, Luca Peruzzotti-Jametti, Tommaso Leonardi, Nunzio Vicario, Daniel Ye, Yang-ja Lee, Dragan Maric, Kory R. Johnson, Yongshan Mou, Aletta Van Den Bosch, Mark Winterbone, Gregory K. Friedman, Robin J.M. Franklin, John M. Hallenbeck, and Stefano Pluchino
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Neural stem cell (NSC)-based therapies hold great promise for treating diseases of the central nervous system (CNS). However, several fundamental problems still need to be overcome to fully exploit the clinical potential of NSC therapeutics. Chief among them is the limited survival of NSC grafts within hostile microenvironments. Methods: Herein, we sought to engineer NSCs in an effort to increase graft survival within ischemic brain lesions via upregulation of global SUMOylation, a post-translational modification critically involved in mediating tolerance to ischemia/reperfusion. Findings: NSCs overexpressing the SUMO E2-conjugase Ubc9 displayed resistance to oxygen-glucose-deprivation/restoration of oxygen/glucose (OGD/ROG) and enhanced neuronal differentiation in vitro, as well as increased survival and neuronal differentiation when transplanted in mice with transient middle cerebral artery occlusion in vivo. Interpretation: Our work highlights a critical role for SUMOylation in NSC biology and identifies a biological pathway that can be targeted to increase the effectiveness of exogenous stem cell medicines in ischemic stroke. Fund: Intramural Research Program of the NINDS/NIH, the Italian Multiple Sclerosis Foundation (FISM), the Bascule Charitable Trust, NIH-IRTA-OxCam and Wellcome Trust Research Training Fellowships. Keywords: Neural stem cells (NSCs), SUMOylation, Ubc9, Ischemia/reperfusion, Stroke, Cell therapy, Regenerative medicine, Cellular engineering
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- 2019
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12. Neural stem cells traffic functional mitochondria via extracellular vesicles.
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Luca Peruzzotti-Jametti, Joshua D Bernstock, Cory M Willis, Giulia Manferrari, Rebecca Rogall, Erika Fernandez-Vizarra, James C Williamson, Alice Braga, Aletta van den Bosch, Tommaso Leonardi, Grzegorz Krzak, Ágnes Kittel, Cristiane Benincá, Nunzio Vicario, Sisareuth Tan, Carlos Bastos, Iacopo Bicci, Nunzio Iraci, Jayden A Smith, Ben Peacock, Karin H Muller, Paul J Lehner, Edit Iren Buzas, Nuno Faria, Massimo Zeviani, Christian Frezza, Alain Brisson, Nicholas J Matheson, Carlo Viscomi, and Stefano Pluchino
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Biology (General) ,QH301-705.5 - Abstract
Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.
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- 2021
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13. Harnessing the Neural Stem Cell Secretome for Regenerative Neuroimmunology
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Cory M. Willis, Alexandra M. Nicaise, Regan Hamel, Vasiliki Pappa, Luca Peruzzotti-Jametti, and Stefano Pluchino
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stem cell secretome ,neural stem cells ,immune modulation ,CNS injury ,extracellular vesicles ,regenerative neuroimmunology ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Increasing evidence foresees the secretome of neural stem cells (NSCs) to confer superimposable beneficial properties as exogenous NSC transplants in experimental treatments of traumas and diseases of the central nervous system (CNS). Naturally produced secretome biologics include membrane-free signaling molecules and extracellular membrane vesicles (EVs) capable of regulating broad functional responses. The development of high-throughput screening pipelines for the identification and validation of NSC secretome targets is still in early development. Encouraging results from pre-clinical animal models of disease have highlighted secretome-based (acellular) therapeutics as providing significant improvements in biochemical and behavioral measurements. Most of these responses are being hypothesized to be the result of modulating and promoting the restoration of key inflammatory and regenerative programs in the CNS. Here, we will review the most recent findings regarding the identification of NSC-secreted factors capable of modulating the immune response to promote the regeneration of the CNS in animal models of CNS trauma and inflammatory disease and discuss the increased interest to refine the pro-regenerative features of the NSC secretome into a clinically available therapy in the emerging field of Regenerative Neuroimmunology.
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- 2020
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14. RNA Nanotherapeutics for the Amelioration of Astroglial Reactivity
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Jayden A. Smith, Alice Braga, Jeroen Verheyen, Silvia Basilico, Sara Bandiera, Clara Alfaro-Cervello, Luca Peruzzotti-Jametti, Dan Shu, Farzin Haque, Peixuan Guo, and Stefano Pluchino
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RNA nanotherapeutics ,astrocytes ,Lipocalin2 ,astrogliosis ,siRNA ,pRNA ,Therapeutics. Pharmacology ,RM1-950 - Abstract
In response to injuries to the CNS, astrocytes enter a reactive state known as astrogliosis, which is believed to be deleterious in some contexts. Activated astrocytes overexpress intermediate filaments including glial fibrillary acidic protein (GFAP) and vimentin (Vim), resulting in entangled cells that inhibit neurite growth and functional recovery. Reactive astrocytes also secrete inflammatory molecules such as Lipocalin 2 (Lcn2), which perpetuate reactivity and adversely affect other cells of the CNS. Herein, we report proof-of-concept use of the packaging RNA (pRNA)-derived three-way junction (3WJ) motif as a platform for the delivery of siRNAs to downregulate such reactivity-associated genes. In vitro, siRNA-3WJs induced a significant knockdown of Gfap, Vim, and Lcn2 in a model of astroglial activation, with a concomitant reduction in protein expression. Knockdown of Lcn2 also led to reduced protein secretion from reactive astroglial cells, significantly impeding the perpetuation of inflammation in otherwise quiescent astrocytes. Intralesional injection of anti-Lcn2-3WJs in mice with contusion spinal cord injury led to knockdown of Lcn2 at mRNA and protein levels in vivo. Our results provide evidence for siRNA-3WJs as a promising platform for ameliorating astroglial reactivity, with significant potential for further functionalization and adaptation for therapeutic applications in the CNS.
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- 2018
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15. Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming
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Joshua D. Bernstock, Daniel Ye, Florian A. Gessler, Yang-ja Lee, Luca Peruzzotti-Jametti, Peter Baumgarten, Kory R. Johnson, Dragan Maric, Wei Yang, Donat Kögel, Stefano Pluchino, and John M. Hallenbeck
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Medicine ,Science - Abstract
Abstract Protein SUMOylation is a dynamic post-translational modification shown to be involved in a diverse set of physiologic processes throughout the cell. SUMOylation has also been shown to play a role in the pathobiology of myriad cancers, one of which is glioblastoma multiforme (GBM). As such, the clinical significance and therapeutic utility offered via the selective control of global SUMOylation is readily apparent. There are, however, relatively few known/effective inhibitors of global SUMO-conjugation. Herein we describe the identification of topotecan as a novel inhibitor of global SUMOylation. We also provide evidence that inhibition of SUMOylation by topotecan is associated with reduced levels of CDK6 and HIF-1α, as well as pronounced changes in cell cycle progression and cellular metabolism, thereby highlighting its putative role as an adjuvant therapy in defined GBM patient populations.
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- 2017
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16. Treatment Challenges of a Primary Vertebral Artery Aneurysm Causing Recurrent Ischemic Strokes
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Davide Strambo, Luca Peruzzotti-Jametti, Aurora Semerano, Giovanna Fanelli, Franco Simionato, Roberto Chiesa, Enrico Rinaldi, Vittorio Martinelli, Giancarlo Comi, Marco Bacigaluppi, and Maria Sessa
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Background. Extracranial vertebral artery aneurysms are a rare cause of embolic stroke; surgical and endovascular therapy options are debated and long-term complication may occur. Case Report. A 53-year-old man affected by neurofibromatosis type 1 (NF1) came to our attention for recurrent vertebrobasilar embolic strokes, caused by a primary giant, partially thrombosed, fusiform aneurysm of the left extracranial vertebral artery. The aneurysm was treated by endovascular approach through deposition of Guglielmi Detachable Coils in the proximal segment of the left vertebral artery. Six years later the patient presented stroke recurrence. Cerebral angiography and Color Doppler Ultrasound well characterized the unique hemodynamic condition developed over the years responsible for the new embolic event: the aneurysm had been revascularized from its distal portion by reverse blood flow coming from the patent vertebrobasilar axis. A biphasic Doppler signal in the left vertebral artery revealed a peculiar behavior of the blood flow, alternately directed to the aneurysm and backwards to the basilar artery. Surgical ligation of the distal left vertebral artery and excision of the aneurysm were thus performed. Conclusion. This is the first described case of NF1-associated extracranial vertebral artery aneurysm presenting with recurrent embolic stroke. Complete exclusion of the aneurysm from the blood circulation is advisable to achieve full resolution of the embolic source.
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- 2017
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17. Astrocyte power fuels neurons during stroke
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Stefano Pluchino, Luca Peruzzotti-Jametti, and Christian Frezza
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Medicine - Published
- 2016
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18. Integrative transcriptomic and metabolic analyses of the mammalian hibernating brain identifies a key role for succinate dehydrogenase in ischemic tolerance
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Joshua D. Bernstock, Cory M. Willis, Monica Emili Garcia-Segura, Edoardo Gaude, Daniela Anni, Yan-ja Lee, Luke W. Thomas, Alva Casey, Nunzio Vicario, Tommaso Leonardi, Alexandra M. Nicaise, Florian A. Gessler, Saef Izzy, Mario R. Buffelli, Jakob Seidlitz, Shriya Srinivasan, Michael P. Murphy, Margaret Ashcroft, Marco Cambiaghi, John M. Hallenbeck, and Luca Peruzzotti-Jametti
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Article - Abstract
Ischemic stroke results in a loss of tissue homeostasis and integrity, the underlying pathobiology of which stems primarily from the depletion of cellular energy stores and perturbation of available metabolites1. Hibernation in thirteen-lined ground squirrels (TLGS),Ictidomys tridecemlineatus, provides a natural model of ischemic tolerance as these mammals undergo prolonged periods of critically low cerebral blood flow without evidence of central nervous system (CNS) damage2. Studying the complex interplay of genes and metabolites that unfolds during hibernation may provide novel insights into key regulators of cellular homeostasis during brain ischemia. Herein, we interrogated the molecular profiles of TLGS brains at different time points within the hibernation cycle via RNA sequencing coupled with untargeted metabolomics. We demonstrate that hibernation in TLGS leads to major changes in the expression of genes involved in oxidative phosphorylation and this is correlated with an accumulation of the tricarboxylic acid (TCA) cycle intermediates citrate, cis-aconitate, and α-ketoglutarate-αKG. Integration of the gene expression and metabolomics datasets led to the identification of succinate dehydrogenase (SDH) as the critical enzyme during hibernation, uncovering a break in the TCA cycle at that level. Accordingly, the SDH inhibitor dimethyl malonate (DMM) was able to rescue the effects of hypoxia on human neuronal cellsin vitroand in mice subjected to permanent ischemic strokein vivo. Our findings indicate that studying the regulation of the controlled metabolic depression that occurs in hibernating mammals may lead to novel therapeutic approaches capable of increasing ischemic tolerance in the CNS.
- Published
- 2023
19. Targeting oncometabolism to maximize immunotherapy in malignant brain tumors
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Joshua D. Bernstock, Kyung-Don Kang, Neil V. Klinger, Hannah E. Olsen, Sam Gary, Stacie K. Totsch, Gelare Ghajar-Rahimi, David Segar, Eric M. Thompson, Victor Darley-Usmar, Bryan T. Mott, Luca Peruzzotti-Jametti, and Gregory K. Friedman
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Cancer Research ,Genetics ,Molecular Biology - Published
- 2022
20. Integrative multi-omics analysis reveals molecular landscape associated with chronic lipid accumulation following contusive spinal cord injury
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Xin-Qiang Yao, Jia-Ying Chen, Zi-Han Yu, Zu-Cheng Huang, Regan Hamel, Jun-Hao Liu, Xing Shen, Yong-Er Wang, Yong-Qiang Zeng, Zhi-Ping Huang, Yan-Meng Lu, Zhi-Tao Zhou, Cui-Ting Liu, Jun-Min Shi, Luca Peruzzotti-Jametti, Stefano Pluchino, Qing-An Zhu, and Jian-Ting Chen
- Abstract
Lipid metabolism is a critical process that occurs in the lipid-rich spinal cord during damage and repair. Here, we integrated ultrastructural characteristics with multi-omics analysis as well as transcriptomic, untargeted, targeted proteomic, lipidomic, and N6-methyladenosine (m6A) epitranscriptomic profiling in a clinically relevant spinal cord injury (SCI) model. We observed lipid accumulation, lysosome-based autophagy of lipid droplets, and remyelination in the lesion of the chronic phase. The analysis also revealed molecular alterations associated with the enhancement of glycolysis, tricarboxylic acid cycle, and fatty acid metabolism, marked increases in triglyceride species with C16:0 fatty acyl chains, and adaptive changes in cholesterol metabolism. These changes included decreased uptake of cholesterol through Mylip upregulation, decreased synthesis through downregulation of Fdps and Hmgcs1, and increased efflux through Apoe upregulation. Among these, Mylip and Hmgcs1 are regulated by m6A methylation. Altogether, our findings revealed endogenous mechanisms in response to microenvironment changes, highlighting the potential of exploring lipid regulators for SCI treatment.
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- 2023
21. Neuroinflammation in Multiple Sclerosis
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Pranathi Prasad, Larissa Roth, Rosana-Bristena Ionescu, Cory Willis, Alexandra Nicaise, Grzegorz Krzak, Luca Peruzzotti-Jametti, and Stefano Pluchino
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- 2023
22. Multiple sclerosis and neuromyelitis optica spectrum disorders
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Rosana-Bristena Ionescu, Cory Willis, Alexandra M. Nicaise, Grzegorz Krzak, Regan Hamel, Luca Peruzzotti-Jametti, and Stefano Pluchino
- Published
- 2023
23. Contributors
- Author
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Samira Abdulai-Saiku, Stanley H. Appel, Arthur P. Arnold, Lisa M. Arnold, Robert M. Arnold, Alexa Bacha, Miroslav 'Misha' Backonja, Zinzi D. Bailey, Lucinda Bateman, David R. Beers, Anna Berti, Mamta Bhatnagar, Devin K. Binder, Marina Boido, Maura Boldrini, David Borsook, Xandra O. Breakefield, Robert H. Brown, Rami Burstein, Eduardo R. Butelman, Louis R. Caplan, S. Chen, Marie-Françoise Chesselet, Stefan Clemens, Paula R. Clemens, Joseph T. Coyle, John C. DeWitt, Dena B. Dubal, Veljko Dubljević, Eva L. Feldman, Beth A. Fischer, M.C. Flux, J.S. Fortin, Angelisa Frasca, Francesca Garbarini, Thomas Gasser, Charles F. Gillespie, Michael S. Gold, Stefan M. Gold, Randi Hagerman, Regan Hamel, Craig Haney, James C. Harris, Sara Hassani, Norman J. Haughey, Vibol Heng, J. Horn, Rosana-Bristena Ionescu, Raffaele Iorio, David J. Irwin, Henry J. Kaminski, Dalia Khammash, Vikram Khurana, Charlotte Kilstrup-Nielsen, Bhumsoo Kim, Boram Kim, Marieke Klein, Nastassja Koen, Glenn T. Konopaske, Joanna A. Korecka, Birgitte Rahbek Kornum, Mary Jeanne Kreek, Krister Kristensson, Grzegorz Krzak, Linda L. Kusner, Nicoletta Landsberger, Edward B. Lee, Tong Li, Paweł P. Liberski, Christine Lochner, Christopher A. Lowry, J. John Mann, Clara Marincowitz, E.A. Mayer, E.D. Mayer, Iris Coates McCall, Louise D. McCullough, Michael J. Meaney, Claudio Melo de Gusmao, Abhishek L. Menesgere, Emmanuel Mignot, William C. Mobley, Mayra Montalvo, Alisha R. Moreland-Capuia, Marco Neppi-Modona, Alexandra M. Nicaise, Rae Nishi, Orna O'Toole, Cassia Overk, Laurie Ozelius, Matthew P. Parsons, H.B. Penticoff, Luca Peruzzotti-Jametti, Owen M. Peters, Allison Peterson, Jessica M. Phan, Sean J. Pittock, Stefano Pluchino, Thad A. Polk, Araya Puwanant, Shreya K. Rajagopal, Vijayalakshmi Ravindranath, Lynn A. Raymond, Brian Reed, Kerry J. Ressler, Diane L. Ritchie, Leah H. Rubin, Stacey A. Sakowski, Mario A. Saporta, Alena V. Savonenko, Helen E. Scharfman, Bruce K. Shapiro, Nutan Sharma, Cayce K. Shaw, Michael E. Shy, Beata Sikorska, Ethan J. Silverman, Roger P. Simon, Kristina Simonyan, Catrina Sims-Robinson, Richard Jay Smeyne, Clay Smith, Colin Smith, Sharan R. Srinivasan, Dan J. Stein, Christopher D. Stephen, Indu Subramanian, Edina Szabo, Alissa A. Thomas, Luis B. Tovar-y-Romo, Arshya Vahabzadeh, Alessandro Vercelli, Ashley Viera-Ortiz, Mitchell T. Wallin, Donna M. Werling, Thomas Wichmann, Clayton A. Wiley, David R. Williams, Cory Willis, Philip C. Wong, Vadim Yuferov, Weihua Zhao, Michael J. Zigmond, and Saša A. Živković
- Published
- 2023
24. Small Extracellular Vesicles Secreted by Nigrostriatal Astrocytes Rescue Cell Death and Preserve Mitochondrial Function in Parkinson's Disease (Adv. Healthcare Mater. 20/2022)
- Author
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Loredana Leggio, Francesca L'Episcopo, Andrea Magrì, María José Ulloa‐Navas, Greta Paternò, Silvia Vivarelli, Carlos A. P. Bastos, Cataldo Tirolo, Nunzio Testa, Salvatore Caniglia, Pierpaolo Risiglione, Fabrizio Pappalardo, Alessandro Serra, Patricia García‐Tárraga, Nuno Faria, Jonathan J. Powell, Luca Peruzzotti‐Jametti, Stefano Pluchino, José Manuel García‐Verdugo, Angela Messina, Bianca Marchetti, and Nunzio Iraci
- Subjects
Biomaterials ,Biomedical Engineering ,Pharmaceutical Science - Published
- 2022
25. A neural stem-cell treatment for progressive multiple sclerosis
- Author
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Stefano Pluchino, Valentina Fossati, and Luca Peruzzotti-Jametti
- Subjects
General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2023
26. Succinate Receptor 1: An Emerging Regulator of Myeloid Cell Function in Inflammation
- Author
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Grzegorz Krzak, Luca Peruzzotti-Jametti, Stefano Pluchino, Cory M. Willis, and Jayden A. Smith
- Subjects
0301 basic medicine ,Myeloid ,Immunology ,Cell ,Regulator ,Inflammation ,Context (language use) ,Biology ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Succinate receptor 1 ,Animals ,Humans ,Immunology and Allergy ,Myeloid Cells ,Tissue homeostasis ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,medicine.symptom ,Signal Transduction ,030215 immunology - Abstract
The rapidly evolving area of immunometabolism has shed new light on the fundamental properties of products and intermediates of cellular metabolism (metabolites), highlighting their key signaling roles in cell-to-cell communication. Recent evidence identifies the succinate-succinate receptor 1 (SUCNR1) axis as an essential regulator of tissue homeostasis. Succinate signaling via SUCNR1 guides divergent responses in immune cells, which are tissue and context dependent. Herein, we explore the main cellular pathways regulated by the succinate-SUCNR1 axis and focus on the biology of SUCNR1 and its roles influencing the function of myeloid cells. Hence, we identify new therapeutic targets and putative therapeutic approaches aimed at resolving detrimental myeloid cell responses in tissues, including those occurring in the persistently inflamed central nervous system (CNS).
- Published
- 2021
27. Promises and Limitations of Neural Stem Cell Therapies for Progressive Multiple Sclerosis
- Author
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Stefano Pluchino, Jayden A. Smith, and Luca Peruzzotti-Jametti
- Subjects
Central Nervous System ,0301 basic medicine ,Central nervous system ,Bioinformatics ,Regenerative medicine ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Neural Stem Cells ,medicine ,Animals ,Humans ,Molecular Biology ,Neuroinflammation ,business.industry ,Multiple sclerosis ,Hematopoietic Stem Cell Transplantation ,Multiple Sclerosis, Chronic Progressive ,medicine.disease ,Neural stem cell ,Transplantation ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Molecular Medicine ,business ,030217 neurology & neurosurgery ,Stem Cell Transplantation - Abstract
Multiple disease-modifying medications with regulatory approval to treat multiple sclerosis (MS) are unable to prevent inflammatory tissue damage in the central nervous system (CNS), and none directly promote repair. Thus, there is an unmet clinical need for therapies that can arrest and reverse the persistent accumulation of disabilities associated with progressive forms of MS (P-MS). Preclinical research has revealed an unexpected ability of neural stem cell (NSC) therapies to provide neurotrophic support and inhibit detrimental host immune responses in vivo following transplantation into the chronically inflamed CNS. We discuss NSC transplantation as a promising therapy for P-MS, elaborate on the necessities of clinical trial validation and formalized usage guidelines, and caution about unscrupulous 'clinics' marketing unproven therapies to patients.
- Published
- 2020
28. Soluble factors influencing the neural stem cell niche in brain physiology, inflammation, and aging
- Author
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Cory M. Willis, Alexandra M. Nicaise, Grzegorz Krzak, Rosana-Bristena Ionescu, Vasiliki Pappa, Andrea D'Angelo, Ravi Agarwal, Maria Repollés-de-Dalmau, Luca Peruzzotti-Jametti, and Stefano Pluchino
- Subjects
Inflammation ,Mammals ,Developmental Neuroscience ,Neurology ,Neural Stem Cells ,Neurogenesis ,Animals ,Brain ,Cell Differentiation ,Stem Cell Niche - Abstract
Within the adult central nervous system (CNS) of most mammals resides a resident stem cell population, known as neural stem cells (NSCs). NSCs are located within specific niches of the CNS and maintain a self-renewal and proliferative capacity to generate new neurons, astrocytes, and oligodendrocytes throughout adulthood. The NSC niches are dynamic and active environments that are within proximity to the systemic circulation and the cerebrospinal fluid (CSF). Therefore, NSCs respond not only to factors present in the local microenvironment of the niche but also to factors present in the systemic macroenvironment. The factors can be soluble forms such as cytokines and chemokines located in the circulation or directly from local cells, such as microglia and astrocytes. Additionally, recent evidence points towards physiological aging and its association with a progressive loss of function and a decline in the self-renewal and regenerative capacities of CNS NSCs, which can be further exacerbated by changes in the local and systemic milieu. This review will highlight the main intrinsic and extrinsic regulators of neural stem cell function under homeostatic and inflammatory conditions including those trafficked within extracellular membrane vesicles. Further, discussion will center around how intrinsic and extrinsic factors impact normal homeostatic functions within the adult brain and in aging.
- Published
- 2021
29. Therapy with mesenchymal stem cell transplantation in multiple sclerosis ready for prime time: Commentary
- Author
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Luca Peruzzotti-Jametti and Stefano Pluchino
- Subjects
Multiple Sclerosis ,Neurology ,Humans ,Neurology (clinical) ,Mesenchymal Stem Cell Transplantation - Published
- 2022
30. Targeting oncometabolism to maximize immunotherapy in malignant brain tumors
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Joshua D, Bernstock, Kyung-Don, Kang, Neil V, Klinger, Hannah E, Olsen, Sam, Gary, Stacie K, Totsch, Gelare, Ghajar-Rahimi, David, Segar, Eric M, Thompson, Victor, Darley-Usmar, Bryan T, Mott, Luca, Peruzzotti-Jametti, and Gregory K, Friedman
- Subjects
Adult ,Oncolytic Virotherapy ,Brain Neoplasms ,Tumor Microenvironment ,Humans ,Glioma ,Immunotherapy ,Child - Abstract
Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicate that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed "tumor immunometabolism". Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase, and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.
- Published
- 2021
31. Subcutaneous cladribine to treat multiple sclerosis: experience in 208 patients
- Author
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Andrea Stennett, Ashok Adams, Amy MacDougall, Eli Silber, Gavin Giovannoni, Luca Peruzzotti-Jametti, Lucia Bianchi, Sharmilee Gnanapavan, Zhifeng Mao, Owen R Pearson, Cris S. Constantinescu, K. Allen-Philbey, Özlem Yildiz, Basil Sharrack, Cesar Álvarez-González, Bruno Gran, Catherine Dalton, Klaus Schmierer, Christine Chapman, Z Khaleeli, Helen Ford, Camilla Blain, Antonio Scalfari, Leonora Fisniku, Stefania De Trane, Sue Pavitt, Gunnar Juliusson, Stewart Webb, Rachel A Farrell, Monica Marta, Miriam Mattoscio, Xia Zhou, Jeremy Hobart, David Baker, Emma C. Tallantyre, Joela Mathews, Karen Chung, and Benjamin Turner
- Subjects
Pharmacology ,medicine.medical_specialty ,business.industry ,Multiple sclerosis ,disease-modifying treatment ,cladribine ,NEPAD ,NEDA ,multiple sclerosis ,medicine.disease ,Dermatology ,Disease course ,Neurology ,treatment access ,medicine ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,business ,Cladribine ,RC346-429 ,Original Research ,medicine.drug - Abstract
Objective: To report on safety and effectiveness of subcutaneous cladribine (Litak®) in multiple sclerosis (MS) patients. Methods: Litak® was offered to MS-patients irrespective of disease course. Litak® 10 mg was administered for 3–4 days during week 1. Based on lymphocyte count at week 4, patients received another 0–3 doses at week 5. A second course was administered 11 months later. Follow-up included adverse events, relapses, expanded disability status scale (EDSS), 9-hole-peg and Timed-25-foot-walking tests, no-evidence-of-disease-activity (NEDA), no-evidence-of-progression-or-active-disease (NEPAD), MRI, cerebrospinal fluid (CSF) neurofilament light chain (NfL), and lymphocyte counts. Results: In all, 208 patients received at least one course of treatment. Age at baseline was 44 (17–72) years and EDSS 0–8.5. Cladribine was generally well tolerated. One myocardial infarction, one breast cancer, and three severe skin reactions occurred without long-term sequelae. Two patients died (one pneumonia, one encephalitis). Lymphopenia grade 3 occurred in 5% and grade 4 in 0.5%. In 94 out of 116 pwMS with baseline and follow-up (BaFU) data after two treatment courses, EDSS remained stable or improved. At 18 months, 64% of patients with relapsing MS and BaFU data ( n = 39) had NEDA. At 19 months, 62% of patients with progressive MS and BaFU data ( n = 13) had NEPAD. Of n = 13 patients whose CSF-NfL at baseline was elevated, 77% were normalised within 12 months. Conclusions: Litak® was well tolerated. Effectiveness in relapsing MS appeared similar to cladribine tablets and was encouraging in progressive MS. Our data suggest cladribine may be safe and effective in MS-patients irrespective of their disease stage.
- Published
- 2021
32. Stem Cell Therapies for Progressive Multiple Sclerosis
- Author
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Stefano Pluchino, Luca Peruzzotti-Jametti, Jayden A. Smith, Alexandra M. Nicaise, Rosana-Bristena Ionescu, Regan Hamel, Nicaise, Alexandra [0000-0001-7160-5988], Peruzzotti Jametti, Luca [0000-0002-9396-5607], Pluchino, Stefano [0000-0002-6267-9472], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Ataxia ,QH301-705.5 ,medicine.medical_treatment ,Review ,Disease ,stem cell therapy ,Cell and Developmental Biology ,neural stem cell ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Biology (General) ,Intensive care medicine ,mesenchymal stem cell ,regenerative neuroimmunology ,business.industry ,Multiple sclerosis ,clinical trial ,Cell Biology ,Stem-cell therapy ,medicine.disease ,Neural stem cell ,Transplantation ,progressive multiple sclerosis ,030104 developmental biology ,Stem cell ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Progressive disease ,Developmental Biology - Abstract
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal degeneration. MS patients typically present with a relapsing-remitting (RR) disease course, manifesting as sporadic attacks of neurological symptoms including ataxia, fatigue, and sensory impairment. While there are several effective disease-modifying therapies able to address the inflammatory relapses associated with RRMS, most patients will inevitably advance to a progressive disease course marked by a gradual and irreversible accrual of disabilities. Therapeutic intervention in progressive MS (PMS) suffers from a lack of well-characterized biological targets and, hence, a dearth of successful drugs. The few medications approved for the treatment of PMS are typically limited in their efficacy toactiveforms of the disease, have little impact on slowing degeneration, and fail to promote repair. In looking to address these unmet needs, the multifactorial therapeutic benefits of stem cell therapies are particularly compelling. Ostensibly providing neurotrophic support, immunomodulation and cell replacement, stem cell transplantation holds substantial promise in combatting the complex pathology of chronic neuroinflammation. Herein, we explore the current state of preclinical and clinical evidence supporting the use of stem cells in treating PMS and we discuss prospective hurdles impeding their translation into revolutionary regenerative medicines.
- Published
- 2021
33. Small Extracellular Vesicles Secreted by Region-specific Astrocytes Ameliorate the Mitochondrial Function in a Cellular Model of Parkinson’s Disease
- Author
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Francesco Pappalardo, Ulloa-Navas Mj, Pierpaolo Risiglione, Stefano Pluchino, Francesca L'Episcopo, Greta Paternò, Nunzio Testa, Silvia Vivarelli, José Manuel García-Verdugo, Nunzio Iraci, Salvatore Caniglia, Loredana Leggio, Bianca Marchetti, Bastos Cap, Andrea Magrì, Luca Peruzzotti-Jametti, Angela Messina, Nuno Faria, and Cataldo Tirolo
- Subjects
Parkinson's disease ,Chemistry ,Dopaminergic ,medicine ,Secretion ,Striatum ,Cellular model ,medicine.disease_cause ,Neuron death ,medicine.disease ,Neuroprotection ,Oxidative stress ,Cell biology - Abstract
Extracellular vesicles (EVs) are emerging as powerful players in cell-to-cell communication both in health and diseased brain. In Parkinson’s disease (PD) – characterized by selective dopaminergic (DAergic) neuron death in ventral midbrain (VMB) and degeneration of DAergic terminals in striatum (STR) – astrocytes (AS) exert dual harmful/protective functions. When activated by chemokine CCL3, AS promote a robust DAergic neuroprotection both in cellular and pre-clinical models of PD, with mechanisms not fully elucidated. Here we used a combination of techniques to characterize AS-EVs derived from VMB and STR, and investigated their potential to exert neuroprotection. First, we show that: (i) AS of both regions secrete small EVs of ~100 nm; (ii) VMB-AS release more EVs per cell than STR-AS under basal conditions; and (iii) only VMB-AS respond to CCL3 by producing more EVs, suggesting differential AS-EV secretion rate according to PD brain region. Next, addressing AS-EV potential against oxidative stress and mitochondrial toxicity, we found that AS-EVs, especially CCL3-AS-EVs, fully counteract H2O2-induced caspase-3 activation. Furthermore, using high resolution respirometry, we demonstrated that AS-EVs rescue the neuronal mitochondrial complex I function impaired by MPP+, with VMB-AS-EVs fully restoring ATP production in MPP+-injured neurons, highlighting a regional diversity of AS-EVs with neuroprotective implications for PD.
- Published
- 2021
34. Neural stem cells traffic functional mitochondria via extracellular vesicles
- Author
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Erika Fernandez-Vizarra, Carlo Viscomi, Ágnes Kittel, Sisareuth Tan, Christian Frezza, Stefano Pluchino, Cristiane Benincá, Nunzio Vicario, Massimo Zeviani, Tommaso Leonardi, Ben Peacock, Paul J. Lehner, Alice Braga, Joshua D. Bernstock, Aletta Van Den Bosch, Jayden A. Smith, Karin H. Muller, Carlos Bastos, Edit I. Buzás, Luca Peruzzotti-Jametti, Giulia Manferrari, Cory M. Willis, Alain Brisson, Nunzio Iraci, Rebecca Rogall, Nuno Faria, Grzegorz Krzak, James C Williamson, Nicholas J Matheson, Iacopo Bicci, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), European Project: 258803, Peruzzotti-Jametti, Luca [0000-0002-9396-5607], Bernstock, Joshua D [0000-0002-7814-3867], Willis, Cory M [0000-0001-7938-7276], Manferrari, Giulia [0000-0001-7062-1142], Rogall, Rebecca [0000-0003-0605-2322], Fernandez-Vizarra, Erika [0000-0002-2469-142X], Williamson, James C [0000-0002-2009-189X], Braga, Alice [0000-0003-3273-9742], van den Bosch, Aletta [0000-0001-8886-8928], Leonardi, Tommaso [0000-0002-4449-1863], Benincá, Cristiane [0000-0001-7933-860X], Vicario, Nunzio [0000-0001-5934-3962], Tan, Sisareuth [0000-0003-3633-6318], Bicci, Iacopo [0000-0001-6994-3857], Iraci, Nunzio [0000-0003-2146-9329], Smith, Jayden A [0000-0003-2307-8452], Peacock, Ben [0000-0002-7823-8719], Muller, Karin H [0000-0003-4693-8558], Brisson, Alain [0000-0003-0342-352X], Matheson, Nicholas J [0000-0002-3318-1851], Apollo - University of Cambridge Repository, Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Bernstock, Joshua D. [0000-0002-7814-3867], Willis, Cory M. [0000-0001-7938-7276], Williamson, James C. [0000-0002-2009-189X], Smith, Jayden A. [0000-0003-2307-8452], Muller, Karin H. [0000-0003-4693-8558], and Matheson, Nicholas J. [0000-0002-3318-1851]
- Subjects
0301 basic medicine ,Central Nervous System ,Proteomics ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Cell Membranes ,Artificial Gene Amplification and Extension ,Mitochondrion ,Outer membrane proteins ,Inbred C57BL ,Exosomes ,Biochemistry ,Nervous System ,Transgenic ,White Blood Cells ,Database and Informatics Methods ,Mice ,0302 clinical medicine ,Neural Stem Cells ,Animal Cells ,Medicine and Health Sciences ,Computer software ,Biology (General) ,Energy-Producing Organelles ,Cells, Cultured ,Phagocytes ,Cultured ,Proteomic Databases ,General Neuroscience ,Neural stem cell ,Cell biology ,Mitochondria ,Polymerase chain reaction ,medicine.anatomical_structure ,Female ,Stem cell ,Cellular Structures and Organelles ,Cellular Types ,Anatomy ,General Agricultural and Biological Sciences ,Research Article ,QH301-705.5 ,Cells ,Immune Cells ,Central nervous system ,Immunology ,Green Fluorescent Proteins ,Mice, Transgenic ,Biology ,Bioenergetics ,Research and Analysis Methods ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Extracellular Vesicles ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Organelle ,medicine ,Animals ,Vesicles ,Molecular Biology Techniques ,Molecular Biology ,Blood Cells ,General Immunology and Microbiology ,Biology and Life Sciences ,Membrane Proteins ,Biological Transport ,Mesenchymal Stem Cells ,Cell Biology ,Microvesicles ,Transplantation ,Mice, Inbred C57BL ,030104 developmental biology ,Biological Databases ,030217 neurology & neurosurgery - Abstract
Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs). EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids, and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs are yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics. Herein, we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells. Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs with conserved membrane potential and respiration. We found that the transfer of these mitochondria from EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of mitochondria from EVs into inflammatory mononuclear phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits. Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases., This study shows that neural stem cells are able to transfer functional mitochondria via extracellular vesicles to target cells both in vitro and in vivo, suggesting that functional mitochondrial transfer via extracellular vesicles is a signaling mechanism used by neural stem cells to modulate the physiology and metabolism of target cells.
- Published
- 2021
35. Therapeutically expanded human regulatory T-cells are super- suppressive due to HIF1A induced expression of CD73
- Author
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Lorna Jarvis, Daniel Rainbow, Valerie Coppard, Sarah Howlett, Jessica Davies, Harpreet Mullay, Joanna Hester, Tom Ashmore, Aletta Van Den Bosch, James Grist, Alasdair Coles, Hani Mousa, Stefano Pluchino, Krishnaa Mahbubani, Julian Griffin, Kourosh Saeb-Parsy, Fadi Issa, Luca Peruzzotti-Jametti, Linda Wicker, and Joanne Jones
- Abstract
The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression
- Published
- 2020
36. Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73
- Author
-
Daniel B. Rainbow, Lorna B. Jarvis, Valerie Coppard, Hani S Mousa, Joanne L. Jones, Alasdair Coles, Zoya Georgieva, Fadi Issa, Kourosh Saeb-Parsy, Krishnaa T. Mahbubani, Stefano Pluchino, Tom Ashmore, Sarah Howlett, Julian L. Griffin, Luca Peruzzotti-Jametti, Linda S. Wicker, Aletta Van Den Bosch, Joanna Hester, Harpreet Kaur Mullay, James T. Grist, Jessica L. Davies, Jarvis, Lorna B [0000-0002-5760-0125], Rainbow, Daniel B [0000-0003-4931-3289], Davies, Jessica L [0000-0002-8888-1441], Hester, Joanna [0000-0002-7466-3849], Pluchino, Stefano [0000-0002-6267-9472], Mahbubani, Krishnaa T [0000-0002-1327-2334], Griffin, Julian L [0000-0003-1336-7744], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Issa, Fadi [0000-0002-8279-7732], Wicker, Linda S [0000-0001-7771-0324], Jones, Joanne L [0000-0003-4974-1371], Apollo - University of Cambridge Repository, Mousa, Hani S [0000-0002-8327-7114], Jarvis, Lorna B. [0000-0002-5760-0125], Rainbow, Daniel B. [0000-0003-4931-3289], Davies, Jessica L. [0000-0002-8888-1441], Mahbubani, Krishnaa T. [0000-0002-1327-2334], Griffin, Julian L. [0000-0003-1336-7744], Wicker, Linda S. [0000-0001-7771-0324], and Jones, Joanne L. [0000-0003-4974-1371]
- Subjects
Male ,Adoptive cell transfer ,Autoimmune diseases ,Medicine (miscellaneous) ,medicine.disease_cause ,T-Lymphocytes, Regulatory ,Graft-versus-host disease ,Autoimmunity ,Transcriptome ,13/1 ,0302 clinical medicine ,Biology (General) ,631/250/24/1313 ,5'-Nucleotidase ,0303 health sciences ,631/250/24/1529 ,631/250/251/1574 ,hemic and immune systems ,Regulatory T cells ,3. Good health ,13/31 ,030220 oncology & carcinogenesis ,631/250/1619/554/1898/1271 ,38/39 ,64/60 ,Female ,General Agricultural and Biological Sciences ,medicine.drug ,QH301-705.5 ,13/106 ,chemical and pharmacologic phenomena ,Biology ,GPI-Linked Proteins ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,13/21 ,medicine ,Humans ,030304 developmental biology ,82 ,82/58 ,Hypoxia-Inducible Factor 1, alpha Subunit ,Adenosine ,Transplantation ,HIF1A ,Gene Expression Regulation ,Anaerobic glycolysis ,Cancer research ,Ex vivo ,Immunosuppression - Abstract
The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression., Jarvis et al demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A)-driven acquisition of CD73 expression, which along with CD39, enables expanded Tregs to convert ATP to immunosuppressive adenosine. Given this, the data suggests that Treg expansion protocols should be optimised for CD39/CD73 co-expression to enhance therapeutic potential.
- Published
- 2020
37. Harnessing the Neural Stem Cell Secretome for Regenerative Neuroimmunology
- Author
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Alexandra M. Nicaise, Regan Hamel, Stefano Pluchino, Luca Peruzzotti-Jametti, Cory M. Willis, Vasiliki Pappa, Apollo - University of Cambridge Repository, Willis, Cory [0000-0001-7938-7276], Nicaise, Alexandra [0000-0001-7160-5988], Peruzzotti Jametti, Luca [0000-0002-9396-5607], and Pluchino, Stefano [0000-0002-6267-9472]
- Subjects
0301 basic medicine ,Cell signaling ,Central nervous system ,Disease ,Review ,Biology ,COVID-19 and cytokine storm syndrome ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Immune system ,Cellular neuroscience ,medicine ,CNS injury ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,neural stem cells ,immune modulation ,regenerative neuroimmunology ,Regeneration (biology) ,stem cell secretome ,Neural stem cell ,030104 developmental biology ,medicine.anatomical_structure ,Neuroimmunology ,Cellular Neuroscience ,extracellular vesicles ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Increasing evidence foresees the secretome of neural stem cells (NSCs) to confer superimposable beneficial properties as exogenous NSC transplants in experimental treatments of traumas and diseases of the central nervous system (CNS). Naturally produced secretome biologics include membrane-free signaling molecules and extracellular membrane vesicles (EVs) capable of regulating broad functional responses. The development of high-throughput screening pipelines for the identification and validation of NSC secretome targets is still in early development. Encouraging results from pre-clinical animal models of disease have highlighted secretome-based (acellular) therapeutics as providing significant improvements in biochemical and behavioral measurements. Most of these responses are being hypothesized to be the result of modulating and promoting the restoration of key inflammatory and regenerative programs in the CNS. Here, we will review the most recent findings regarding the identification of NSC-secreted factors capable of modulating the immune response to promote the regeneration of the CNS in animal models of CNS trauma and inflammatory disease and discuss the increased interest to refine the pro-regenerative features of the NSC secretome into a clinically available therapy in the emerging field of Regenerative Neuroimmunology.
- Published
- 2020
38. Time-resolved single-cell RNAseq profiling identifies a novel Fabp5-expressing subpopulation of inflammatory myeloid cells in chronic spinal cord injury
- Author
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Katherine Ridley, David H. Rowitch, Stefano Pluchino, Veronica Testa, Luca Peruzzotti-Jametti, John C. Marioni, Bryan Yu, and Regan Hamel
- Subjects
Innate immune system ,business.industry ,Cell ,medicine.disease ,Pathogenesis ,Lesion ,medicine.anatomical_structure ,Myeloid cells ,Cancer research ,Medicine ,Cytotoxic T cell ,medicine.symptom ,business ,Wound healing ,Spinal cord injury - Abstract
Innate immune responses following spinal cord injury (SCI) participate in early secondary pathogenesis and wound healing events. Here, we used time-resolved scRNAseq to map transcriptional profiles of SC tissue-resident and infiltrating myeloid cells post-SCI.Our work identifies a novel subpopulation of Fabp5+ inflammatory myeloid cells, comprising both resident and infiltrating cells and displaying a delayed cytotoxic profile at the lesion epicentre, which may serve as a target for future therapeutics.
- Published
- 2020
39. Systematic approach to selecting licensed drugs for repurposing in the treatment of progressive multiple sclerosis
- Author
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Alerie Guzman de la Fuente, Brooke Lumicisi, Sorrel R. B. Bickley, Judy Beveridge, Ranjit Kaur, Jennifer Robertson, Patrick Camilleri, Debbie Ainslie, Alasdair Coles, Stefano Pluchino, Anna Williams, Emma Gray, Gavin Giovannoni, Luca Peruzzotti-Jametti, Denise C. Fitzgerald, Kenneth Smith, Matthew Craner, David Baker, Alan Palmer, Alastair Wilkins, Nick G Cunniffe, Khue Anh Vuong, David Kozlowski, Don J. Mahad, Alan Rothaul, Lyndsey Shellard, Lorraine Hazlehurst, Raj Kapoor, Björn Neumann, Cunniffe, Nick [0000-0002-7562-2838], Baker, David [0000-0002-8872-8711], Giovannoni, Gavin [0000-0001-9995-1700], and Apollo - University of Cambridge Repository
- Subjects
medicine.medical_specialty ,MEDLINE ,Lamotrigine ,Multiple sclerosis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Intensive care medicine ,Oxcarbazepine ,Repurposing ,030304 developmental biology ,0303 health sciences ,business.industry ,Drug Repositioning ,Multiple Sclerosis, Chronic Progressive ,medicine.disease ,3. Good health ,Metformin ,Clinical trial ,Psychiatry and Mental health ,Clemastine ,Drug Evaluation ,Surgery ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
ObjectiveTo establish a rigorous, expert-led, evidence-based approach to the evaluation of licensed drugs for repurposing and testing in clinical trials of people with progressive multiple sclerosis (MS).MethodsWe long-listed licensed drugs with evidence of human safety, blood–brain barrier penetrance and demonstrable efficacy in at least one animal model, or mechanistic target, agreed by a panel of experts and people with MS to be relevant to the pathogenesis of progression. We systematically reviewed the preclinical and clinical literature for each compound, condensed this into a database of summary documents and short-listed drugs by scoring each one of them. Drugs were evaluated for immediate use in a clinical trial, and our selection was scrutinised by a final independent expert review.ResultsFrom a short list of 55 treatments, we recommended four treatments for immediate testing in progressive MS: R-α-lipoic acid, metformin, the combination treatment of R-α-lipoic acid and metformin, and niacin. We also prioritised clemastine, lamotrigine, oxcarbazepine, nimodipine and flunarizine.ConclusionsWe report a standardised approach for the identification of candidate drugs for repurposing in the treatment of progressive MS.
- Published
- 2020
40. Transplantation of induced neural stem cells (iNSCs) into chronically demyelinated corpus callosum ameliorates motor deficits
- Author
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Sandra Rizzi, Regina C. Armstrong, Bernard J. Dardzinski, Frank Edenhofer, Alexandru Korotcov, Genevieve M. Sullivan, Luca Peruzzotti-Jametti, Joshua D. Bernstock, Asamoah Bosomtwi, Stefano Pluchino, Andrew K. Knutsen, Peruzzotti Jametti, Luca [0000-0002-9396-5607], Pluchino, Stefano [0000-0002-6267-9472], Apollo - University of Cambridge Repository, and Armstrong, Regina C. [0000-0001-7296-6750]
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Induced Pluripotent Stem Cells ,Neuropathology ,Motor Activity ,lcsh:RC346-429 ,Corpus Callosum ,Pathology and Forensic Medicine ,Multiple sclerosis ,Cuprizone ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Magnetic resonance imaging ,0302 clinical medicine ,medicine ,Animals ,Remyelination ,lcsh:Neurology. Diseases of the nervous system ,030304 developmental biology ,Magnetization transfer ratio ,Neural stem cells ,0303 health sciences ,business.industry ,Research ,Neurodegeneration ,Cell Differentiation ,Reprogramming ,medicine.disease ,Neural stem cell ,Oligodendrocyte ,3. Good health ,Astrogliosis ,Mice, Inbred C57BL ,Transplantation ,Disease Models, Animal ,Oligodendroglia ,Diffusion tensor imaging ,medicine.anatomical_structure ,Astrocytes ,Neurology (clinical) ,Stem cell therapeutics ,business ,030217 neurology & neurosurgery - Abstract
Multiple Sclerosis (MS) causes neurologic disability due to inflammation, demyelination, and neurodegeneration. Immunosuppressive treatments can modify the disease course but do not effectively promote remyelination or prevent long term neurodegeneration. As a novel approach to mitigate chronic stage pathology, we tested transplantation of mouse induced neural stem cells (iNSCs) into the chronically demyelinated corpus callosum (CC) in adult mice. Male C57BL/6 mice fed 0.3% cuprizone for 12 weeks exhibited CC atrophy with chronic demyelination, astrogliosis, and microglial activation. Syngeneic iNSCs were transplanted into the CC after ending cuprizone and perfused for neuropathology 2 weeks later. Magnetic resonance imaging (MRI) sequences for magnetization transfer ratio (MTR), diffusion-weighted imaging (T2), and diffusion tensor imaging (DTI) quantified CC pathology in live mice before and after iNSC transplantation. Each MRI technique detected progressive CC pathology. Mice that received iNSCs had normalized DTI radial diffusivity, and reduced astrogliosis post-imaging. A motor skill task that engages the CC is Miss-step wheel running, which demonstrated functional deficits from cuprizone demyelination. Transplantation of iNSCs resulted in marked recovery of running velocity. Neuropathology after wheel running showed that iNSC grafts significantly increased host oligodendrocytes and proliferating oligodendrocyte progenitors, while modulating axon damage. Transplanted iNSCs differentiated along astrocyte and oligodendrocyte lineages, without myelinating, and many remained neural stem cells. Our findings demonstrate the applicability of neuroimaging and functional assessments for pre-clinical interventional trials during chronic demyelination and detect improved function from iNSC transplantation. Directly reprogramming fibroblasts into iNSCs facilitates the future translation towards exogenous autologous cell therapies.
- Published
- 2020
41. Neural stem cells traffic functional mitochondria via extracellular vesicles to correct mitochondrial dysfunction in target cells
- Author
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Nunzio Vicario, Massimo Zeviani, Carlos Bastos, Rebecca Rogall, Joshua D. Bernstock, Christian Frezza, Sisareuth Tan, Erika Fernandez-Vizarra, James C Williamson, Carlo Viscomi, Stefano Pluchino, Aletta Van Den Bosch, Cristiane Benincá, Luca Peruzzotti-Jametti, Alice Braga, Paul J. Lehner, Tommaso Leonardi, Jayden A. Smith, Edit I. Buzás, Ágnes Kittel, Nunzio Iraci, Nicholas J Matheson, Giulia Manferrari, Iacopo Bicci, Nuno Faria, and Alain Brisson
- Subjects
0303 health sciences ,Central nervous system ,Endogeny ,Biology ,Mitochondrion ,Proteomics ,Neural stem cell ,Cell biology ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Organelle ,medicine ,Stem cell ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Neural stem cell (NSC) transplantation induces recovery in animal models of central nervous system (CNS) diseases. Although the replacement of lost endogenous cells was originally proposed as the primary healing mechanism of NSC grafts, it is now clear that transplanted NSCs operate via multiple mechanisms, including the horizontal exchange of therapeutic cargoes to host cells via extracellular vesicles (EVs).EVs are membrane particles trafficking nucleic acids, proteins, metabolites and metabolic enzymes, lipids and entire organelles. However, the function and the contribution of these cargoes to the broad therapeutic effects of NSCs is yet to be fully understood. Mitochondrial dysfunction is an established feature of several inflammatory and degenerative CNS disorders, most of which are potentially treatable with exogenous stem cell therapeutics.Herein we investigated the hypothesis that NSCs release and traffic functional mitochondria via EVs to restore mitochondrial function in target cells.Untargeted proteomics revealed a significant enrichment of mitochondrial proteins spontaneously released by NSCs in EVs. Morphological and functional analyses confirmed the presence of ultrastructurally intact mitochondria within EVs (Mito-EVs) with conserved membrane potential and respiration. We found that the transfer of Mito-EVs to mtDNA-deficient L929 Rho0 cells rescued mitochondrial function and increased Rho0 cell survival. Furthermore, the incorporation of Mito-EVs into inflammatory professional phagocytes restored normal mitochondrial dynamics and cellular metabolism and reduced the expression of pro-inflammatory markers in target cells. When transplanted in an animal model of multiple sclerosis, exogenous NSCs actively transferred mitochondria to mononuclear phagocytes and induced a significant amelioration of clinical deficits.Our data provide the first evidence that NSCs deliver functional mitochondria to target cells via Mito-EVs, paving the way for the development of novel (a)cellular approaches aimed at restoring mitochondrial dysfunction not only in multiple sclerosis, but also in degenerative neurological diseases.
- Published
- 2020
42. The therapeutic potential of exogenous adult stem cells for the injured central nervous system
- Author
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Bryan Yu, Carola Rutigliani, Regan Hamel, Jayden Smith, Luca Peruzzotti-Jametti, Alice Braga, and Stefano Pluchino
- Subjects
Transplantation ,business.industry ,Mesenchymal stem cell ,Medicine ,Stem cell ,business ,Induced pluripotent stem cell ,Embryonic stem cell ,Neuroscience ,Reprogramming ,Neural stem cell ,Adult stem cell - Abstract
The multimodal therapeutic properties of stem-cell therapies hold considerable promise for addressing the complex pathologies arising from damage to the central nervous system (CNS). Stem cells derived from embryonic or fetal sources are burdened with safety, practical, and ethical concerns, so there is considerable interest in stem cells that can be obtained from adult tissues. Transplantation of adult stem cells, be they of somatic origin (e.g., neural stem cells or mesenchymal stromal cells) or acquired through reprogramming of somatic cells (e.g., induced pluripotent stem cells), has been shown to yield myriad benefits at the molecular, anatomical, and functional levels in preclinical animal models of various CNS disorders. However, clinical translation has thus far been impeded by only modest efficacy outcomes in clinical trials, speaking to a need for greater consistency and controls in such studies. We provide a brief overview of adult stem cells and summarize the findings of their preclinical and clinical therapeutic applications in the injured CNS.
- Published
- 2020
43. List of Contributors
- Author
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Armando Almeida, Rita C. Assunção-Silva, Sandra Barata-Antunes, Assumpcio Bosch, Nicholas M. Boulis, Alice Braga, Bing Chen, Miguel Chillon, Jorge E. Collazos-Castro, João Cortinhas, Jianwu Dai, Ignacio Delgado-Martínez, Jaume del Valle, Madalena Esteves, Razan Faraj, Thais Federici, Michael G. Fehlings, Aline M. Fernandes, Miguel Gago, Guillermo García-Alías, Julian L. Gendreau, Eduardo D. Gomes, Alex Greven, Laureen D. Hachem, Regan Hamel, R.M. Ichiyama, Pavla Jendelová, Kristýna Kárová, Kristýna Kekulová, R.W.P. Kissane, Zuzana Kočí, Šárka Kubinová, Hugo Leite-Almeida, Mariah Lelos, Zhijia Liang, Rui Lima, Sara Monteiro Lopes, Alvaro Machado, Cláudia R. Marques, Susana Monteiro, Pedro M.D. Moreno, Xavier Navarro, Itse Onuwaje, Ana P. Pêgo, Inês M. Pereira, Luís Pereira de Almeida, Luca Peruzzotti-Jametti, James B. Phillips, Stefano Pluchino, Sofia Rocha, Nataliya Romanyuk, Carola Rutigliani, António J. Salgado, Nadine Correia Santos, Nuno A. Silva, Jayden A. Smith, Barbora Svobodová, Fábio G. Teixeira, Andreia Teixeira-Castro, Pavlos Texakalidis, Muhibullah S. Tora, Lucia Machova Urdzíková, Zhifeng Xiao, Bryan Yu, and Yannan Zhao
- Published
- 2020
44. Evaluation of RGD functionalization in hybrid hydrogels as 3D neural stem cell culture systems
- Author
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Emanuele Mauri, Luca Peruzzotti-Jametti, Nunzio Vicario, Stefano Pluchino, Filippo Rossi, Alessandro Sacchetti, Peruzzotti Jametti, Luca [0000-0002-9396-5607], Pluchino, Stefano [0000-0002-6267-9472], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Scaffold ,Biomedical Engineering ,02 engineering and technology ,Cell fate determination ,Inbred C57BL ,Mice ,03 medical and health sciences ,Neural Stem Cells ,Tissue engineering ,Cell Adhesion ,Animals ,General Materials Science ,Cell adhesion ,Cell Proliferation ,Tissue Engineering ,Tissue Scaffolds ,Cell growth ,Chemistry ,Hydrogels ,021001 nanoscience & nanotechnology ,Neural stem cell ,Cell biology ,Mice, Inbred C57BL ,Transplantation ,Female ,Oligopeptides ,Protein Binding ,030104 developmental biology ,Self-healing hydrogels ,0210 nano-technology - Abstract
The use of neural stem cells (NSCs) in cell therapy has become a powerful tool used for the treatment of central nervous system diseases, including traumatic brain and spinal cord injuries. However, a significant drawback is related to the limited viability after transplantation in situ. The design of three-dimensional (3D) scaffolds that are capable of resembling the architecture and physico-chemical features of an extracellular environment could be a suitable approach to improve cell survival and preserve their cellular active phase over time. In this study, we investigated NSC adhesion and proliferation in hydrogel systems. In particular, we evaluated the effect of RGD binding domains on cell fate within the polymeric scaffold. The introduction of a tripeptide via hydrogel chemical functionalization improved the percentage of proliferating cells until 8 days after seeding when compared to the unmodified scaffold. The beneficial effects of this 3D culture system was further evident when compared to a NSC monolayer (2D) culture, resulting in an approximately 40% increase in cells in the active phases at 4 and 8 days, and maintained a difference of 25% until 21 days after seeding.
- Published
- 2018
45. Extracellular vesicles are independent metabolic units with asparaginase activity
- Author
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Carlos Bastos, Tommaso Leonardi, Ana S. H. Costa, Nunzio Iraci, Maurizio Gelati, Joshua D. Bernstock, Stefano Pluchino, Chiara Cossetti, Harpreet K Saini, Edoardo Gaude, Anton J. Enright, Nuno Faria, Luigi Occhipinti, Angelo L. Vescovi, Christian Frezza, Luca Peruzzotti-Jametti, Iraci, N, Gaude, E, Leonardi, T, Costa, A, Cossetti, C, Peruzzotti Jametti, L, Bernstock, J, Saini, H, Gelati, M, Vescovi, A, Bastos, C, Faria, N, Occhipinti, L, Enright, A, Frezza, C, Pluchino, S, Iraci, Nunzio [0000-0003-2146-9329], Peruzzotti-Jametti, Luca [0000-0002-9396-5607], Bernstock, Joshua D [0000-0002-7814-3867], Frezza, Christian [0000-0002-3293-7397], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,chemistry.chemical_classification ,Extracellular Vesicle ,Chemistry ,Cell Biology ,Metabolism ,Bioinformatics ,Models, Biological ,Glutaminase activity ,3. Good health ,Cell biology ,Extracellular Vesicles ,03 medical and health sciences ,030104 developmental biology ,Metabolomics ,Enzyme ,Asparaginase ,Asparagine ,Stem cell ,Progenitor cell ,Molecular Biology ,health care economics and organizations ,Function (biology) - Abstract
Extracellular vesicles (EVs) are membrane particles involved in the exchange of a broad range of bioactive molecules between cells and the microenvironment. Although it has been shown that cells can traffic metabolic enzymes via EVs, much remains to be elucidated with regard to their intrinsic metabolic activity. Accordingly, herein we assessed the ability of neural stem/progenitor cell (NSC)-derived EVs to consume and produce metabolites. Our metabolomics and functional analyses both revealed that EVs harbor L-asparaginase activity, catalyzed by the enzyme asparaginase-like protein 1 (Asrgl1). Critically, we show that Asrgl1 activity is selective for asparagine and is devoid of glutaminase activity. We found that mouse and human NSC EVs traffic Asrgl1. Our results demonstrate, for the first time, that NSC EVs function as independent metabolic units that are able to modify the concentrations of critical nutrients, with the potential to affect the physiology of their microenvironment.
- Published
- 2017
46. SUMOylation promotes survival and integration of neural stem cell grafts in ischemic stroke
- Author
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Luca Peruzzotti-Jametti, Kory R. Johnson, Mark Winterbone, Yongshan Mou, Yang-ja Lee, Aletta Van Den Bosch, Joshua D. Bernstock, Gregory K. Friedman, Dragan Maric, Nunzio Vicario, Robin J.M. Franklin, John M. Hallenbeck, Tommaso Leonardi, Stefano Pluchino, Daniel Ye, Bernstock, Joshua [0000-0002-7814-3867], Peruzzotti Jametti, Luca [0000-0002-9396-5607], Leonardi, Tommaso [0000-0002-4449-1863], Franklin, Robin [0000-0001-6522-2104], Pluchino, Stefano [0000-0002-6267-9472], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Male ,Research paper ,SUMO protein ,Gene Expression ,Regenerative medicine ,Transgenic ,Cell therapy ,Mice ,0302 clinical medicine ,Neural Stem Cells ,Neural stem cells (NSCs) ,Ubc9 ,Stroke ,Neurons ,Cell Cycle ,Cellular engineering ,Ischemia/reperfusion ,SUMOylation ,Animals ,Biomarkers ,Computational Biology ,Energy Metabolism ,Gene Expression Profiling ,Glucose ,Mice, Transgenic ,Neurogenesis ,Oxygen ,Signal Transduction ,Stem Cell Transplantation ,Sumoylation ,Ubiquitin-Conjugating Enzymes ,Cell Survival ,General Medicine ,Neural stem cell ,030220 oncology & carcinogenesis ,Stem cell ,Ischemia ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Downregulation and upregulation ,medicine ,business.industry ,medicine.disease ,030104 developmental biology ,nervous system ,business ,Neuroscience - Abstract
Background Neural stem cell (NSC)-based therapies hold great promise for treating diseases of the central nervous system (CNS). However, several fundamental problems still need to be overcome to fully exploit the clinical potential of NSC therapeutics. Chief among them is the limited survival of NSC grafts within hostile microenvironments. Methods Herein, we sought to engineer NSCs in an effort to increase graft survival within ischemic brain lesions via upregulation of global SUMOylation, a post-translational modification critically involved in mediating tolerance to ischemia/reperfusion. Findings NSCs overexpressing the SUMO E2-conjugase Ubc9 displayed resistance to oxygen-glucose-deprivation/restoration of oxygen/glucose (OGD/ROG) and enhanced neuronal differentiation in vitro, as well as increased survival and neuronal differentiation when transplanted in mice with transient middle cerebral artery occlusion in vivo. Interpretation Our work highlights a critical role for SUMOylation in NSC biology and identifies a biological pathway that can be targeted to increase the effectiveness of exogenous stem cell medicines in ischemic stroke. Fund Intramural Research Program of the NINDS/NIH, the Italian Multiple Sclerosis Foundation (FISM), the Bascule Charitable Trust, NIH-IRTA-OxCam and Wellcome Trust Research Training Fellowships.
- Published
- 2018
47. Treatment Challenges of a Primary Vertebral Artery Aneurysm Causing Recurrent Ischemic Strokes
- Author
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Marco Bacigaluppi, Maria Sessa, Davide Strambo, Roberto Chiesa, G. Fanelli, Aurora Semerano, Luca Peruzzotti-Jametti, Vittorio Martinelli, Giancarlo Comi, Enrico Rinaldi, Franco Simionato, Strambo, Davide, Peruzzotti Jametti, Luca, Semerano, Aurora, Fanelli, Giovanna, Simionato, Franco, Chiesa, Roberto, Rinaldi, Enrico, Martinelli, Vittorio, Comi, Giancarlo, Bacigaluppi, Marco, and Sessa, Maria
- Subjects
medicine.medical_specialty ,Vertebral artery ,Hemodynamics ,Case Report ,Fusiform Aneurysm ,030204 cardiovascular system & hematology ,lcsh:RC346-429 ,03 medical and health sciences ,0302 clinical medicine ,Aneurysm ,medicine.artery ,medicine ,Basilar artery ,cardiovascular diseases ,Neurofibromatosis ,lcsh:Neurology. Diseases of the nervous system ,medicine.diagnostic_test ,business.industry ,Blood flow ,medicine.disease ,Surgery ,cardiovascular system ,Radiology ,General Agricultural and Biological Sciences ,business ,030217 neurology & neurosurgery ,Cerebral angiography - Abstract
Background. Extracranial vertebral artery aneurysms are a rare cause of embolic stroke; surgical and endovascular therapy options are debated and long-term complication may occur. Case Report. A 53-year-old man affected by neurofibromatosis type 1 (NF1) came to our attention for recurrent vertebrobasilar embolic strokes, caused by a primary giant, partially thrombosed, fusiform aneurysm of the left extracranial vertebral artery. The aneurysm was treated by endovascular approach through deposition of Guglielmi Detachable Coils in the proximal segment of the left vertebral artery. Six years later the patient presented stroke recurrence. Cerebral angiography and Color Doppler Ultrasound well characterized the unique hemodynamic condition developed over the years responsible for the new embolic event: the aneurysm had been revascularized from its distal portion by reverse blood flow coming from the patent vertebrobasilar axis. A biphasic Doppler signal in the left vertebral artery revealed a peculiar behavior of the blood flow, alternately directed to the aneurysm and backwards to the basilar artery. Surgical ligation of the distal left vertebral artery and excision of the aneurysm were thus performed. Conclusion. This is the first described case of NF1-associated extracranial vertebral artery aneurysm presenting with recurrent embolic stroke. Complete exclusion of the aneurysm from the blood circulation is advisable to achieve full resolution of the embolic source.
- Published
- 2017
48. The neural stem cell secretome and its role in brain repair
- Author
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Luca Peruzzotti-Jametti, Stefano Pluchino, Cory M. Willis, Alexandra M. Nicaise, Willis, Cory [0000-0001-7938-7276], Nicaise, Alexandra [0000-0001-7160-5988], Peruzzotti Jametti, Luca [0000-0002-9396-5607], Pluchino, Stefano [0000-0002-6267-9472], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Central nervous system ,Disease ,Biology ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Central Nervous System Diseases ,Neurotrophic factors ,medicine ,Animals ,Humans ,Molecular Biology ,Secretome ,Progenitor ,Neural stem cells ,General Neuroscience ,Stem cell transplantation ,Extracellular vesicles ,Neural stem cell ,Transplantation ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Neurology (clinical) ,Stem cell ,Neuroscience ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
Compelling evidence from experimental animal disease models and early-phase clinical trials identifies the transplantation of neural progenitor/stem cells (NSCs) as a viable path towards the development of clinically applicable exogenous stem cell therapies. Building from current advances in the field of NSC biology and following the positive outcomes of NSC transplantation studies, the contemporary view is that transplanted NSCs act as local 'factories' capable of producing and secreting a wide array of immune and neurotrophic factors. This has launched a 'stem cell race' to identify the mechanisms behind stem-cell mediated repair in what has been labeled the paracrine hypothesis. This hypothesis proposes that NSC grafts act as a natural source of potent biologics capable of modulating and promoting the restoration of several key functions in the central nervous system (CNS) tissue following acute or chronic tissue damage. Investigators have been inspired to examine novel ways to harness and utilize the pro-regenerative properties of NSC therapies as an alternative approach to a more classical (small molecule based) treatment of CNS diseases. In this review, we will discuss the most recent findings of human NSC (hNSCs) transplants in experimental animal models of CNS diseases that identify of hNSC-secreted factors, including those trafficked within extracellular membrane vesicles (EVs), and the outcomes of recent clinical trials utilizing hNSC therapeutics in CNS diseases.
- Published
- 2020
49. Interleukin-4 induced 1 (IL4I1) promotes central nervous system remyelination
- Author
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Luca Peruzzotti-Jametti and Stefano Pluchino
- Subjects
0301 basic medicine ,Multiple sclerosis ,T cell ,Central nervous system ,Neurodegeneration ,Multiple sclerosis research ,Inflammation ,Biology ,medicine.disease ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,Immunology ,medicine ,Neurology (clinical) ,medicine.symptom ,Remyelination ,030217 neurology & neurosurgery - Abstract
This scientific commentary refers to ‘IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation’, by Psachoulia et al. (doi:10.1093/brain/aww254) . Multiple sclerosis is an inflammatory demyelinating disease of the CNS characterized by infiltration of immune cells and progressive damage to myelin sheaths and axons (Lorscheider et al. , 2016). Most patients initially develop relapsing-remitting disease (RRMS), in which acute neurological deficits are interspersed with periods of partial or complete recovery. However, up to 65% of patients with RRMS eventually develop secondary progressive multiple sclerosis (SPMS), in which disability increases continually. Conversion to SPMS is associated with a relatively poor prognosis, in part due to the limited effectiveness of disease-modifying therapies in the progressive phase (Lorscheider et al. , 2016). This in turn partly reflects the complex interactions between the multiple pathophysiological mechanisms responsible for demyelination and neurodegeneration. However, there is also compelling evidence that a decline in regenerative capacity occurs in the brain in chronic multiple sclerosis, possibly due to dysregulation of inflammation (Fitzner and Simons, 2010). Unravelling the mechanisms that link the immune system with CNS damage and repair therefore represents both a challenge and an opportunity for multiple sclerosis research. In this issue of Brain , Psachoulia et al. (2016) exploit a published remyelination transcriptome obtained from laser capture microdissected CNS lesions induced in the rodent CNS by lysolecithin/lysophosphatidylcholine (LPC) (Huang et al. , 2011), to identify novel markers of remyelination. Of the more than 8000 differentially regulated genes, Il4i1 , a phenylalanine oxidase secreted mainly by myeloid antigen presenting cells (APCs), was among the most strongly upregulated (4-fold increase at 14 days versus 5 days post-lesion). In situ hybridization demonstrated that Il4i1 was predominantly expressed in cells with morphology reminiscent of foamy macrophages, beginning as early as 10–14 days post-lesion, a …
- Published
- 2016
50. Targeting Mitochondrial Metabolism in Neuroinflammation: Towards a Therapy for Progressive Multiple Sclerosis
- Author
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Stefano Pluchino, Luca Peruzzotti-Jametti, Peruzzotti Jametti, Luca [0000-0002-9396-5607], Pluchino, Stefano [0000-0002-6267-9472], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Central Nervous System ,Toluidines ,Dimethyl Fumarate ,Hydroxybutyrates ,Inflammation ,Mitochondrion ,neuroinflammation ,Electron Transport ,03 medical and health sciences ,Immune system ,Nitriles ,Medicine ,Humans ,Molecular Targeted Therapy ,Molecular Biology ,Mononuclear Phagocyte System ,Neuroinflammation ,Innate immune system ,business.industry ,Multiple sclerosis ,Neurodegeneration ,Neurodegenerative Diseases ,Multiple Sclerosis, Chronic Progressive ,medicine.disease ,Immunity, Innate ,macrophages ,3. Good health ,Mitochondria ,immune metabolism ,progressive multiple sclerosis ,030104 developmental biology ,Cell metabolism ,Crotonates ,Immunology ,Molecular Medicine ,Microglia ,medicine.symptom ,business ,Glymphatic System ,Metabolic Networks and Pathways ,Signal Transduction ,Stem Cell Transplantation - Abstract
The lack of effective treatment options for chronic neurological conditions, such as multiple sclerosis (MS), highlights the need to re-evaluate disease pathophysiology in the process of identifying novel therapeutic targets. The persistent activation of mononuclear phagocytes (MPs) is one of the major drivers of neurodegeneration and it sustains central nervous system (CNS) damage. Mitochondrial metabolism influences the activity of MPs, and the metabolites that they produce have key signalling roles in inflammation. However, how changes in immune cell metabolism sustain a chronic state of neuroinflammation is not fully understood. Novel molecular and cellular therapies for chronic neuroinflammation should be developed to target mitochondrial metabolism in innate immune cells to prevent secondary neurological damage and the accumulation of irreversible disability in patients.
- Published
- 2018
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