5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, with additional pathophysiological involvement of non-neuronal cells such as microglia. The commonest ALS-associated genetic variant is a hexanucleotide repeat expansion (HRE) mutation in C9orf72. Here, we study its consequences for microglial function using human iPSC-derived microglia. By RNA-sequencing, we identify enrichment of pathways associated with immune cell activation and cyto-/chemokines in C9orf72 HRE mutant microglia versus healthy controls, most prominently after LPS priming. Specifically, LPS-primed C9orf72 HRE mutant microglia show consistently increased expression and release of matrix metalloproteinase-9 (MMP9). LPS-primed C9orf72 HRE mutant microglia are toxic to co-cultured healthy motor neurons, which is ameliorated by concomitant application of an MMP9 inhibitor. Finally, we identify release of dipeptidyl peptidase-4 (DPP4) as a marker for MMP9-dependent microglial dysregulation in co-culture. These results demonstrate cellular dysfunction of C9orf72 HRE mutant microglia, and a non-cell-autonomous role in driving C9orf72-ALS pathophysiology in motor neurons through MMP9 signaling.

          Abstract

          The role of microglia in amyotrophic lateral sclerosis (ALS) is unclear. Here, the authors show that iPSC microglia from C9orf72-ALS patients are toxic to motor neurons and identify microglial MMP9 as a potential therapeutic target.

          Related collections

          Most cited references45

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2

          In comparative high-throughput sequencing assays, a fundamental task is the analysis of count data, such as read counts per gene in RNA-seq, for evidence of systematic changes across experimental conditions. Small replicate numbers, discreteness, large dynamic range and the presence of outliers require a suitable statistical approach. We present DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates. This enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression. The DESeq2 package is available at http://www.bioconductor.org/packages/release/bioc/html/DESeq2.html. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0550-8) contains supplementary material, which is available to authorized users.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Fiji: an open-source platform for biological-image analysis.

            Fiji is a distribution of the popular open-source software ImageJ focused on biological-image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image-processing algorithms. Fiji facilitates the transformation of new algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              clusterProfiler: an R package for comparing biological themes among gene clusters.

              Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis. Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters. The analysis module and visualization module were combined into a reusable workflow. Currently, clusterProfiler supports three species, including humans, mice, and yeast. Methods provided in this package can be easily extended to other species and ontologies. The clusterProfiler package is released under Artistic-2.0 License within Bioconductor project. The source code and vignette are freely available at http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html.
                Bookmark

                Author and article information

                Contributors
                sally.cowley@path.ox.ac.uk
                kevin.talbot@ndcn.ox.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                22 September 2023
                22 September 2023
                2023
                : 14
                : 5898
                Affiliations
                [1 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Oxford Motor Neuron Disease Centre, Nuffield Department of Clinical Neurosciences, , University of Oxford, John Radcliffe Hospital, ; Oxford, OX3 9DU UK
                [2 ]Kavli Institute for Nanoscience Discovery, University of Oxford, Dorothy Crowfoot Hodgkin Building, ( https://ror.org/052gg0110) Oxford, OX1 3QU UK
                [3 ]Chinese Academy of Medical Sciences (CAMS), CAMS Oxford Institute (COI), Nuffield Department of Medicine, University of Oxford, ( https://ror.org/052gg0110) Oxford, OX3 7FZ UK
                [4 ]Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics, University of Oxford, Dorothy Crowfoot Hodgkin Building, ( https://ror.org/052gg0110) Oxford, OX1 3QX UK
                [5 ]Molecular Neurodegeneration Research Group, Nuffield Department of Clinical Neurosciences, University of Oxford, Dorothy Crowfoot Hodgkin Building, ( https://ror.org/052gg0110) Oxford, OX1 3QU UK
                [6 ]UK Dementia Research Institute at UCL and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, ( https://ror.org/02wedp412) London, WCIN 3BG UK
                [7 ]James and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of Oxford, ( https://ror.org/052gg0110) Oxford, OX1 3RE UK
                Author information
                http://orcid.org/0000-0002-5159-5070
                http://orcid.org/0009-0004-1314-3518
                http://orcid.org/0000-0003-0146-1821
                http://orcid.org/0000-0001-5054-9016
                http://orcid.org/0000-0003-0776-6431
                http://orcid.org/0000-0002-6820-5534
                http://orcid.org/0000-0001-6691-580X
                http://orcid.org/0000-0003-0267-3180
                http://orcid.org/0000-0003-0297-6675
                http://orcid.org/0000-0001-5490-1697
                Article
                41603
                10.1038/s41467-023-41603-0
                10517114
                37736756
                c54fe5c6-7398-4e60-b77e-b69add109082
                © Springer Nature Limited 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 9 February 2023
                : 6 September 2023
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000406, Motor Neurone Disease Association (MNDA);
                Award ID: Talbot/Apr22/889-791
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000719, Oxford University | St. John's College, University of Oxford (St John's College, University of Oxford);
                Funded by: FundRef https://doi.org/10.13039/501100000265, RCUK | Medical Research Council (MRC);
                Award ID: MR/N013468/1
                Award ID: MR/N013468/1
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000272, DH | National Institute for Health Research (NIHR);
                Funded by: FundRef https://doi.org/10.13039/100004440, Wellcome Trust (Wellcome);
                Award ID: 102176/Z/13/Z
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000038, Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (Conseil de Recherches en Sciences Naturelles et en Génie du Canada);
                Award ID: PGSD3-517039-2018
                Award Recipient :
                Funded by: Oxford University | St. John's College, University of Oxford (St John's College, University of Oxford)
                Funded by: FundRef https://doi.org/10.13039/501100000691, Academy of Medical Sciences;
                Award ID: SGL025\1095
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100000304, Parkinson's UK;
                Award ID: J-1403
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004211, Oxford University | Oxford Martin School, University of Oxford;
                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2023

                Uncategorized
                amyotrophic lateral sclerosis,microglia,induced pluripotent stem cells
                Uncategorized
                amyotrophic lateral sclerosis, microglia, induced pluripotent stem cells

                Comments

                Comment on this article