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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data for 2-month-old wild type and Tfam-SCKO (MPZ-Tfam KO) sciatic nerves

ABSTRACT: Gene expression analysis of 2-month-old Ctrl and Tfam-SCKO mice. At this age mitochondrial function is disrupted in the Schwann cells of Tfam-SCKO mice ,but their nerves display only very limited pathology. Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells, SCs) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response through actions of heme-regulated inhibitor kinase (HRI), and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines, an intermediate of fatty acid b-oxidation. Importantly, we show that acylcarnitines are released from SCs and induce axonal degeneration. A maladaptive integrated stress response as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies. Total RNA samples were prepared by isolating and pooling RNA from three different 2-month-old MPZ-Tfam KO and Ctrl mice. 2 replicates per genotype were used in this experiment and they were prepared entirely independently.

ORGANISM(S): Mus musculus

SUBMITTER: Nobish Varghese

PROVIDER: E-GEOD-44605 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression data for 2-month-old wild type and Tfam-SCKO (MPZ-Tfam KO) sciatic nerves

Project description:Gene expression analysis of 2-month-old Ctrl and Tfam-SCKO mice. At this age mitochondrial function is disrupted in the Schwann cells of Tfam-SCKO mice ,but their nerves display only very limited pathology. Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells, SCs) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response through actions of heme-regulated inhibitor kinase (HRI), and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines, an intermediate of fatty acid b-oxidation. Importantly, we show that acylcarnitines are released from SCs and induce axonal degeneration. A maladaptive integrated stress response as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies.

2013-03-13 | GSE44605 | GEO

Molecular effects of Vitamin C treatment in MSC80 cells, a suitable Schwann cell model

Project description:Schwann cells (SCs) are not only decisive to produce the axon-wrapping myelin sheath thus ensuring a proper nerve conduction but also exhibit with trophic function and can direct repair mechanisms of the peripheral nervous system. Consequently, suitable and well-characterized SC in vitro models are needed to perform appropriate pre-clinical studies including the investigation of the complex biochemical adaptations occurring in the peripheral nervous system (PNS) under different (patho)physiological conditions. MSC80 cells represent a SC line derived from mouse used in laboratories as a suitable in vitro system for neuropathological studies. As a comprehensive MSC80 protein catalogue remained elusive, here we introduce the most abundant 9532 proteins identified via mass spectrometry based protein analytics and thus provide the most comprehensive SC protein catalogue published thus far. Hereby, not only proteins causative for inherited neuropathies were covered but it has also been demonstrated that apart from cytoplasmic and nuclear proteins, mitochondrial proteins and such belonging to the protein processing machinery are very well covered. Moreover, we addressed the suitability of MSC80 to examine molecular effect of a drug-treatment by analyzing the proteomic signature of Vitamin C-treated MSC80 cells. Proteomic findings along with further immunological and functional experiments support the concept of a beneficial role influence of Vitamin C on oxidative stress and identified TMX1 as an oxidative stress protective factor in SC which might represent a promising target for therapeutic intervention of PNS disorders with marked oxidative stress burden such as diabetic neuropathy.

2018-08-13 | PXD006910 | Pride

Comparative proteomic analysis of exosomes derived from endothelial cells and Schwann cells

Project description:Exosomes derived from endothelial cells and Schwann cells have been employed as novel treatments of neurological diseases, including peripheral neuropathy. Exosomal cargo plays a critical role in mediating recipient cell function. In this study, we thus performed a comprehensive proteomic analysis of exosomes derived from healthy mouse dermal microvascular endothelial cells (EC-Exo) and healthy mouse Schwann cells (SC-Exo). We detected 1,817and 1,579 proteins in EC-Exo and SC-Exo, respectively. Among them, 1506 proteins were present in both EC-Exo and SC-Exo, while 311 and 73 proteins were detected only in EC-Exo and SC-Exo, respectively. Bioinformatic analysis revealed that EC-Exo enriched proteins were involved in the neurovascular function, while SC-Exo enriched proteins were related to lipid metabolism. Western blot analysis of 14 enriched proteins revealed that EC-Exo contained proteins involved in mediating endothelial function such as delta-like 4 (DLL4) and endothelial NOS (NOS3), whereas SC-Exo had proteins involved in mediating glial function such as apolipoprotein A-I (APOA1) and phospholipid transfer protein (PLTP). Collectively, the present study indicates cargo protein profiles are distinct between EC-Exo and SC-Exo, suggesting potential roles of EC-Exo and SC-Exo mainly in mediating neurovascular and myelin functions, respectively.

2023-08-20 | PXD041547 | Pride

Schwann cell plasticity regulates neuroblastic tumor cell differentiation - phosphoproteomics

Project description:The remarkable plasticity of Schwann cells (SCs) is essential for nerve regeneration but also contributes to neuropathies and cancer progression. It has not yet been investigated whether the adaptive potential of SCs is manifested in stromal, tumor associated SCs characteristically found within a benign subtype of neuroblastic tumors (NBTs). We here performed transcriptome profiling of human NBTs, rich and poor in SC stroma, as well as human injured nerves, rich in repair SCs, revealing that stromal SCs exhibit a repair SC characteristic gene expression signature. In turn, primary repair SCs had a pro-differentiating and anti-proliferative effect on NBT cell lines after direct and trans-well co-culture. Within the pool of secreted stromal/repair SC factors, we identified EGFL8, a matricellular protein with so far undescribed function, to induce neuronal differentiation of aggressive NBT cells. EGFL8 expression further correlated with favorable tumor stage and increased patient survival. Our findings suggest that stromal SCs exert nerve repair associated functions in the tumor-environment and underline the therapeutic value of SC-derived factors for aggressive, SC stroma-poor NBTs.

2021-01-04 | PXD022217 | Pride

Schwann cell plasticity regulates neuroblastic tumor cell differentiation

2021-01-13 | PXD018267 | Pride

New schwann cell markers identified by gene profiling analysis after axonal contact

Project description:Elucidating the genes regulated during cell-cell communication remains fascinating considering the importance of cell recognition and downstream signaling through development and in many diseases. In the peripheral nervous system, the interaction between Schwann cells (SCs) and axons is crucial as it allows their survival and induces SCs to differentiate and engage a process of myelination. To get further insight the molecular mechanisms resulting from this cell interaction, comparative gene analysis between SCs and SCs co-cultured with DRG neurons were performed and led us to identify a set of 32 genes regulated in SCs in the early stage of neuron-SC contact. Expression of several candidates were analyzed by QPCR during development and we demonstrate using a blocking antibody approach in an in vitro myelination assay that one candidate was not only upregulated in response to axonal contact but also controls peripheral myelination. Three biological replicates each in dye swap for 22k slides and two biological replicates each in dye swap for NeuroDev2

2011-01-15 | E-GEOD-17366 | biostudies-arrayexpress

Role of Rnf40-dependent histone monoubiquitination in peripheral nervous system myelination [RNA-Seq]

Project description:To address the role of monoubiquitination of histone H2B at lysine 120 (H2Bub1), we inactivated the responsible E3 ligase by deleting Rnf40 in developing Schwann cells. Rnf40 becomes important for proper Schwann cell development shortly before and during differentiation. Its absence in Schwann cells leads to a peripheral neuropathy. RNA-Seq studies were performed on sciatic nerves from control mice and mice with a Schwann cell-specific deletion of Rnf40 to analyze changes in gene expression. These revealed substantial changes in the expression of genes associated with myelination, lipid metabolism and cell adhesion.

2020-07-13 | GSE146629 | GEO

Comparison of human skin- and nerve-derived Schwann cells reveals many similarities and subtle genomic and functional differences

Project description:Skin is an easily accessible tissue and a rich source of Schwann cells (SCs). Toward potential clinical application of autologous SC therapies, we aim to improve the reliability and specificity of our protocol to obtain SCs from small skin samples. As well, to explore potential functional distinctions between skin-derived SCs (Sk-SCs) and nerve-derived SCs (N-SCs), we used single-cell RNA-sequencing and a series of in vitro and in vivo assays. Our results showed that Sk-SCs expressed typical SC markers. Single-cell sequencing of Sk- and N-SCs revealed an overwhelming overlap in gene expression with the exception of HLA genes which were preferentially up-regulated in Sk-SCs. In vitro, both cell types exhibited similar levels of proliferation, migration, uptake of myelin debris and readily associated with neurites when co-cultured with human iPSC-induced motor neurons. Both exhibited ensheathment of multiple neurites and early phase of myelination, especially in N-SCs. Interestingly, dorsal root ganglion (DRG) neurite outgrowth assay showed substantially more complexed neurite outgrowth in DRGs exposed to Sk-SC conditioned media compared to those from N-SCs. Multiplex ELISA array revealed shared growth factor profiles, but Sk-SCs expressed a higher level of VEGF. Transplantation of Sk- and N-SCs into injured peripheral nerve in nude rats and NOD-SCID mice showed close association of both SCs to regenerating axons. Myelination of rodent axons was observed infrequently by N-SCs, but absent in Sk-SC xenografts. Overall, our results showed that Sk-SCs share near-identical properties to N-SCs but with subtle differences that could potentially enhance their therapeutic utility.

2022-07-07 | GSE125422 | GEO

Single-cell transcriptomic analysis links non-myelinating Schwann cells to pro-inflammatory response in the lung [bulk RNA-Seq]

Project description:The lung is a barrier tissue with constant exposure to the inhaled environment. Therefore, innate immunity against particulates and pathogens is of critical importance to maintain tissue homeostasis. While the lung harbors both myelinating and non-myelinating Schwann cells (NMSCs), NMSCs represent the abundant Schwann cell (SC) population in the lung. However, their contribution to lung physiology remains largely unknown. Here, we used the human glial fibrillary acidic protein promoter (GFAP) driving tdTomato expression in mice to identify SCs in the peripheral nervous system (PNS) and determine their location within the lung. Single-cell transcriptomic analysis revealed the existence of two NMSC populations (NMSC1 and NMSC2) that may participate in pathogen recognition. We demonstrated that these pulmonary SCs produce chemokines and cytokines upon lipopolysaccharide (LPS) stimulation using in vitro conditions. Furthermore, we challenged mouse lungs with LPS and found that NMSC1 exhibits an enriched pro-inflammatory response among all SC subtypes. Collectively, these findings define the molecular profiles of lung SCs and suggest a potential role for NMSCs in lung inflammation.

2023-06-28 | GSE235905 | GEO

Single-cell transcriptomic analysis links non-myelinating Schwann cells to pro-inflammatory response in the lung [scRNA-seq]

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