Multiple sclerosis (MS) is a neuroinflammatory disease whose pathogenesis remains unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid involved in multiple immune cell functions and ...dysregulated in MS. Its receptor LPA
1
is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the genetic deletion and pharmaceutical inhibition of LPA
1
in the mouse MS model, experimental autoimmune encephalomyelitis (EAE). LPA
1
expression was analyzed in EAE mice and MS patient immune cells. The effect of LPA and LPA
1
on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA
1
activity induces milder clinical EAE course and that
Lpar1
expression in peripheral blood mononuclear cells (PBMC) correlates with onset of relapses and severity in EAE. We see the same over-expression in PBMC from MS patients during relapse compared with progressive forms of the disease and in stimulated monocyte-derived macrophages. LPA induced a proinflammatory-like response in macrophages through LPA
1
, providing a plausible way in which LPA and LPA
1
dysregulation can lead to the inflammation in MS. These data show a new mechanism of LPA signaling in the MS pathogenesis, prompting further research into its use as a therapeutic target biomarker.
Pelizaeus-Merzbacher disease (PMD) results from an X-linked misexpression of proteolipid protein 1 (PLP1). This leukodystrophy causes severe hypomyelination with progressive inflammation, leading to ...neurological dysfunctions and shortened life expectancy. While no cure exists for PMD, experimental cell-based therapy in the dysmyelinated shiverer model suggested that human oligodendrocyte progenitor cells (hOPCs) or human neural precursor cells (hNPCs) are promising candidates to treat myelinopathies. However, the fate and restorative advantages of human NPCs/OPCs in a relevant model of PMD has not yet been addressed. Using a model of Plp1 overexpression, resulting in demyelination with progressive inflammation, we compared side-by-side the therapeutic benefits of intracerebrally grafted hNPCs and hOPCs. Our findings reveal equal integration of the donor cells within presumptive white matter tracks. While the onset of exogenous remyelination was earlier in hOPCs-grafted mice than in hNPC-grafted mice, extended lifespan occurred only in hNPCs-grafted animals. This improved survival was correlated with reduced neuroinflammation (microglial and astrocytosis loads) and microglia polarization toward M2-like phenotype followed by remyelination. Thus modulation of neuroinflammation combined with myelin restoration is crucial to prevent PMD pathology progression and ensure successful rescue of PMD mice. These findings should help to design novel therapeutic strategies combining immunomodulation and stem/progenitor cell-based therapy for disorders associating hypomyelination with inflammation as observed in PMD.
Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. ...Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.
Boundary cap cells (BC), which express the transcription factor Krox20, participate in the formation of the boundary between the central nervous system and the peripheral nervous system. To study BC ...stemness, we developed a method to purify and amplify BC in vitro from Krox20Cre/âº, R26RYFP/⺠mouse embryos. We show that BC progeny are EGF/FGF2-responsive, form spheres, and express neural crest markers. Upon growth factor withdrawal, BC progeny gave rise to multiple neural crest and CNS lineages. Transplanted into the developing murine forebrain, they successfully survived, migrated, and integrated within the host environment. Surprisingly, BC progeny generated exclusively CNS cells, including neurons, astrocytes, and myelin-forming oligodendrocytes. In vitro experiments indicated that a sequential combination of ventralizing morphogens and glial growth factors was necessary to reprogram BC into oligodendrocytes. Thus, BC progeny are endowed with differentiation plasticity beyond the peripheral nervous system. The demonstration that CNS developmental cues can reprogram neural crest-derived stem cells into CNS derivatives suggests that BC could serve as a source of cell type-specific lineages, including oligodendrocytes, for cell-based therapies to treat CNS disorders.
Identifying the nodes able to drive the state of a network is crucial to
understand, and eventually control, biological systems. Despite recent advances,
such identification remains difficult because ...of the huge number of equivalent
controllable configurations, even in relatively simple networks. Based on the
evidence that in many applications it is essential to test the ability of
individual nodes to control a specific target subset, we develop a fast and
principled method to identify controllable driver-target configurations in
sparse and directed networks. We demonstrate our approach on simulated networks
and experimental gene networks to characterize macrophage dysregulation in human
subjects with multiple sclerosis.
We introduce an optimized heuristic, called stepwise target controllability, to
quantify the centrality of a candidate driver node to influence the state of a
network target set. We use this method to study macrophage gene network
alterations in multiple sclerosis. We show that multiple sclerosis is
characterized by a global loss of gene coactivation and that this is due to the
dysregulation of few molecules along the driver-target pathways. These findings
provide new insights into the macrophage network mechanisms underlying the
pathophysiology of multiple sclerosis and provide fresh tools for the study of
driver-target controllability in complex networked systems.
Schwann cell (SC) transplantation is currently being discussed as a strategy that may promote functional recovery in patients with multiple sclerosis (MS) and other inflammatory demyelinating ...diseases of the central nervous system (CNS). However this assumes they will not only survive but also remyelinate demyelinated axons in the chronically inflamed CNS. To address this question we investigated the fate of transplanted SCs in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in the Dark Agouti rat; an animal model that reproduces the complex inflammatory demyelinating immunopathology of MS. We now report that SCs expressing green fluorescent protein (GFP-SCs) allografted after disease onset not only survive but also migrate to remyelinate lesions in the inflamed CNS. GFP-SCs were detected more frequently in the parenchyma after direct injection into the spinal cord, than via intra-thecal delivery into the cerebrospinal fluid. In both cases the transplanted cells intermingled with astrocytes in demyelinated lesions, aligned with axons and by twenty one days post transplantation had formed Pzero protein immunoreactive internodes. Strikingly, GFP-SCs transplantation was associated with marked decrease in clinical disease severity in terms of mortality; all GFP-SCs transplanted animals survived whilst 80% of controls died within 40 days of disease.
The loss of myelin, a major element involved in the saltatory conduction of the electrical impulse of the nervous system, is a major target of current research. Serious long-term disabilities are ...observed in patients with demyelinating disease of the central nervous system, such as multiple sclerosis. New therapeutic strategies aimed at overcoming myelin damage and axonal loss focus on the repair potential of myelin-forming cells. This review examines the use of peripheral myelin-forming cells, the Schwann cells, to promote myelin repair. NEUROSCIENTIST 13(4):383—391, 2007. DOI: 10.1177/1073858407300762
Regularized Generalized Canonical Correlation Analysis (RGCCA) is a general statistical framework for multiblock data analysis. RGCCA enables deciphering relationships between several sets of ...variables and subsumes many well-known multivariate analysis methods as special cases. However, RGCCA only deals with vector-valued blocks, disregarding their possible higher-order structures. This paper presents Tensor GCCA (TGCCA), a new method for analyzing higher-order tensors with canonical vectors admitting an orthogonal rank-R CP decomposition. Moreover, two algorithms for TGCCA, based on whether a separable covariance structure is imposed or not, are presented along with convergence guarantees. The efficiency and usefulness of TGCCA are evaluated on simulated and real data and compared favorably to state-of-the-art approaches.
•Propose TGCCA, a new optimization problem that extends many multiblock methods to the tensor case.•Provide algorithms to solve TGCCA with convergence guarantees.•Validate and compare the method to state-of-the-art methods on simulated and real datasets.
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