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C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9
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...
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Published in: | Nature communications 2023-09, Vol.14 (1), p.5898-5898, Article 5898 |
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creator | Vahsen, Björn F. Nalluru, Sumedha Morgan, Georgia R. Farrimond, Lucy Carroll, Emily Xu, Yinyan Cramb, Kaitlyn M. L. Amein, Benazir Scaber, Jakub Katsikoudi, Antigoni Candalija, Ana Carcolé, Mireia Dafinca, Ruxandra Isaacs, Adrian M. Wade-Martins, Richard Gray, Elizabeth Turner, Martin R. Cowley, Sally A. Talbot, Kevin |
description | 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.
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. |
doi_str_mv | 10.1038/s41467-023-41603-0 |
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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.
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.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/s41467-023-41603-0</identifier><identifier>PMID: 37736756</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/100 ; 13/106 ; 14/19 ; 38/91 ; 631/378/1689/1285 ; 631/378/2596/1953 ; 631/532/2064/2158 ; Amyotrophic lateral sclerosis ; Amyotrophic Lateral Sclerosis - genetics ; C9orf72 Protein - genetics ; Cell activation ; Cell culture ; Chemokines ; Coculture Techniques ; Gelatinase B ; Gene sequencing ; Genetic diversity ; Genetic variance ; Humanities and Social Sciences ; Humans ; Immune system ; Induced Pluripotent Stem Cells ; Inflammation ; Lipopolysaccharides ; Matrix metalloproteinase ; Matrix Metalloproteinase 9 - genetics ; Matrix metalloproteinases ; Metalloproteinase ; Microglia ; Motor Neurons ; multidisciplinary ; Mutants ; Neurodegenerative Diseases ; Neurons ; Pathophysiology ; Priming ; Regulatory sequences ; Science ; Science (multidisciplinary) ; Therapeutic targets</subject><ispartof>Nature communications, 2023-09, Vol.14 (1), p.5898-5898, Article 5898</ispartof><rights>The Author(s) 2023</rights><rights>2023. Springer Nature Limited.</rights><rights>The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Springer Nature Limited 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-a024f2b1838df7d1d65df89638b9c9227fa81e89ce5113f1d3c7293091d1fc483</citedby><cites>FETCH-LOGICAL-c541t-a024f2b1838df7d1d65df89638b9c9227fa81e89ce5113f1d3c7293091d1fc483</cites><orcidid>0000-0002-5159-5070 ; 0009-0004-1314-3518 ; 0000-0003-0146-1821 ; 0000-0003-0297-6675 ; 0000-0003-0776-6431 ; 0000-0001-5054-9016 ; 0000-0003-0267-3180 ; 0000-0001-6691-580X ; 0000-0001-5490-1697 ; 0000-0002-6820-5534</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2867177440/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2867177440?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37736756$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vahsen, Björn F.</creatorcontrib><creatorcontrib>Nalluru, Sumedha</creatorcontrib><creatorcontrib>Morgan, Georgia R.</creatorcontrib><creatorcontrib>Farrimond, Lucy</creatorcontrib><creatorcontrib>Carroll, Emily</creatorcontrib><creatorcontrib>Xu, Yinyan</creatorcontrib><creatorcontrib>Cramb, Kaitlyn M. L.</creatorcontrib><creatorcontrib>Amein, Benazir</creatorcontrib><creatorcontrib>Scaber, Jakub</creatorcontrib><creatorcontrib>Katsikoudi, Antigoni</creatorcontrib><creatorcontrib>Candalija, Ana</creatorcontrib><creatorcontrib>Carcolé, Mireia</creatorcontrib><creatorcontrib>Dafinca, Ruxandra</creatorcontrib><creatorcontrib>Isaacs, Adrian M.</creatorcontrib><creatorcontrib>Wade-Martins, Richard</creatorcontrib><creatorcontrib>Gray, Elizabeth</creatorcontrib><creatorcontrib>Turner, Martin R.</creatorcontrib><creatorcontrib>Cowley, Sally A.</creatorcontrib><creatorcontrib>Talbot, Kevin</creatorcontrib><title>C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>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.
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.</description><subject>13/100</subject><subject>13/106</subject><subject>14/19</subject><subject>38/91</subject><subject>631/378/1689/1285</subject><subject>631/378/2596/1953</subject><subject>631/532/2064/2158</subject><subject>Amyotrophic lateral sclerosis</subject><subject>Amyotrophic Lateral Sclerosis - genetics</subject><subject>C9orf72 Protein - genetics</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Chemokines</subject><subject>Coculture Techniques</subject><subject>Gelatinase B</subject><subject>Gene sequencing</subject><subject>Genetic diversity</subject><subject>Genetic variance</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Immune system</subject><subject>Induced Pluripotent Stem Cells</subject><subject>Inflammation</subject><subject>Lipopolysaccharides</subject><subject>Matrix metalloproteinase</subject><subject>Matrix Metalloproteinase 9 - genetics</subject><subject>Matrix metalloproteinases</subject><subject>Metalloproteinase</subject><subject>Microglia</subject><subject>Motor Neurons</subject><subject>multidisciplinary</subject><subject>Mutants</subject><subject>Neurodegenerative Diseases</subject><subject>Neurons</subject><subject>Pathophysiology</subject><subject>Priming</subject><subject>Regulatory sequences</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Therapeutic targets</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp9kktv1DAUhSMEolXpH2CBLLFhE_D1I7ZXqBrxqDQVlQpry-PHNKPEHuykov8eT1NKywIvbMv3nM-v0zSvAb8HTOWHwoB1osWEtgw6TFv8rDkmmEELgtDnj-ZHzWkpO1wbVSAZe9kcUSFoJ3h33PiVSjkI0p6tr9D1PJqI-surFRp7m9N26A0y2aN9Tm0fw2DG0Uwp3yITHZrSr97WHtnU2nmY5uwdGlOto-jnnGJBN9V_cXGpXjUvghmKP70fT5ofnz99X31t19--nK_O1q3lDKbWYMIC2YCk0gXhwHXcBak6KjfKKkJEMBK8VNZzABrAUSuIoliBg2CZpCfN-cJ1yez0Pvejybc6mV7fLaS81SZPvR28po4D50RK7ggzJCi2cYJ72oVgKKMH1seFtZ83o3fWxymb4Qn0aSX213qbbjRgDgKAVcK7e0JOP2dfJj32xfphMNGnuWgiOwmEYKyq9O0_0l2ac6xvdVAJEIIxXFVkUdW_KSX78HAawPqQCr2kQtdU6LtU6IPpzeN7PFj-ZKAK6CIotRS3Pv_d-z_Y393ewHQ</recordid><startdate>20230922</startdate><enddate>20230922</enddate><creator>Vahsen, Björn F.</creator><creator>Nalluru, Sumedha</creator><creator>Morgan, Georgia R.</creator><creator>Farrimond, Lucy</creator><creator>Carroll, Emily</creator><creator>Xu, Yinyan</creator><creator>Cramb, Kaitlyn M. 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L. ; Amein, Benazir ; Scaber, Jakub ; Katsikoudi, Antigoni ; Candalija, Ana ; Carcolé, Mireia ; Dafinca, Ruxandra ; Isaacs, Adrian M. ; Wade-Martins, Richard ; Gray, Elizabeth ; Turner, Martin R. ; Cowley, Sally A. ; Talbot, Kevin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-a024f2b1838df7d1d65df89638b9c9227fa81e89ce5113f1d3c7293091d1fc483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>13/100</topic><topic>13/106</topic><topic>14/19</topic><topic>38/91</topic><topic>631/378/1689/1285</topic><topic>631/378/2596/1953</topic><topic>631/532/2064/2158</topic><topic>Amyotrophic lateral sclerosis</topic><topic>Amyotrophic Lateral Sclerosis - genetics</topic><topic>C9orf72 Protein - genetics</topic><topic>Cell activation</topic><topic>Cell culture</topic><topic>Chemokines</topic><topic>Coculture Techniques</topic><topic>Gelatinase B</topic><topic>Gene sequencing</topic><topic>Genetic diversity</topic><topic>Genetic variance</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Immune system</topic><topic>Induced Pluripotent Stem Cells</topic><topic>Inflammation</topic><topic>Lipopolysaccharides</topic><topic>Matrix metalloproteinase</topic><topic>Matrix Metalloproteinase 9 - genetics</topic><topic>Matrix metalloproteinases</topic><topic>Metalloproteinase</topic><topic>Microglia</topic><topic>Motor Neurons</topic><topic>multidisciplinary</topic><topic>Mutants</topic><topic>Neurodegenerative Diseases</topic><topic>Neurons</topic><topic>Pathophysiology</topic><topic>Priming</topic><topic>Regulatory sequences</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Therapeutic targets</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vahsen, Björn F.</creatorcontrib><creatorcontrib>Nalluru, Sumedha</creatorcontrib><creatorcontrib>Morgan, Georgia R.</creatorcontrib><creatorcontrib>Farrimond, Lucy</creatorcontrib><creatorcontrib>Carroll, Emily</creatorcontrib><creatorcontrib>Xu, Yinyan</creatorcontrib><creatorcontrib>Cramb, Kaitlyn M. 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L.</au><au>Amein, Benazir</au><au>Scaber, Jakub</au><au>Katsikoudi, Antigoni</au><au>Candalija, Ana</au><au>Carcolé, Mireia</au><au>Dafinca, Ruxandra</au><au>Isaacs, Adrian M.</au><au>Wade-Martins, Richard</au><au>Gray, Elizabeth</au><au>Turner, Martin R.</au><au>Cowley, Sally A.</au><au>Talbot, Kevin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2023-09-22</date><risdate>2023</risdate><volume>14</volume><issue>1</issue><spage>5898</spage><epage>5898</epage><pages>5898-5898</pages><artnum>5898</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><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.
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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>37736756</pmid><doi>10.1038/s41467-023-41603-0</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-5159-5070</orcidid><orcidid>https://orcid.org/0009-0004-1314-3518</orcidid><orcidid>https://orcid.org/0000-0003-0146-1821</orcidid><orcidid>https://orcid.org/0000-0003-0297-6675</orcidid><orcidid>https://orcid.org/0000-0003-0776-6431</orcidid><orcidid>https://orcid.org/0000-0001-5054-9016</orcidid><orcidid>https://orcid.org/0000-0003-0267-3180</orcidid><orcidid>https://orcid.org/0000-0001-6691-580X</orcidid><orcidid>https://orcid.org/0000-0001-5490-1697</orcidid><orcidid>https://orcid.org/0000-0002-6820-5534</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 2041-1723 |
ispartof | Nature communications, 2023-09, Vol.14 (1), p.5898-5898, Article 5898 |
issn | 2041-1723 2041-1723 |
language | eng |
recordid | cdi_doaj_primary_oai_doaj_org_article_3d51552885d24a2f94bd75e36ffa3438 |
source | Publicly Available Content Database; Nature Journals Online; PubMed Central; Springer Nature - nature.com Journals - Fully Open Access |
subjects | 13/100 13/106 14/19 38/91 631/378/1689/1285 631/378/2596/1953 631/532/2064/2158 Amyotrophic lateral sclerosis Amyotrophic Lateral Sclerosis - genetics C9orf72 Protein - genetics Cell activation Cell culture Chemokines Coculture Techniques Gelatinase B Gene sequencing Genetic diversity Genetic variance Humanities and Social Sciences Humans Immune system Induced Pluripotent Stem Cells Inflammation Lipopolysaccharides Matrix metalloproteinase Matrix Metalloproteinase 9 - genetics Matrix metalloproteinases Metalloproteinase Microglia Motor Neurons multidisciplinary Mutants Neurodegenerative Diseases Neurons Pathophysiology Priming Regulatory sequences Science Science (multidisciplinary) Therapeutic targets |
title | C9orf72-ALS human iPSC microglia are pro-inflammatory and toxic to co-cultured motor neurons via MMP9 |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T06%3A11%3A37IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_doaj_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=C9orf72-ALS%20human%20iPSC%20microglia%20are%20pro-inflammatory%20and%20toxic%20to%20co-cultured%20motor%20neurons%20via%20MMP9&rft.jtitle=Nature%20communications&rft.au=Vahsen,%20Bj%C3%B6rn%20F.&rft.date=2023-09-22&rft.volume=14&rft.issue=1&rft.spage=5898&rft.epage=5898&rft.pages=5898-5898&rft.artnum=5898&rft.issn=2041-1723&rft.eissn=2041-1723&rft_id=info:doi/10.1038/s41467-023-41603-0&rft_dat=%3Cproquest_doaj_%3E2868122009%3C/proquest_doaj_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c541t-a024f2b1838df7d1d65df89638b9c9227fa81e89ce5113f1d3c7293091d1fc483%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2867177440&rft_id=info:pmid/37736756&rfr_iscdi=true |