دورية أكاديمية
Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition.
العنوان: | Human motor units in microfluidic devices are impaired by FUS mutations and improved by HDAC6 inhibition. |
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المؤلفون: | Stoklund Dittlau K; KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium., Krasnow EN; KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium., Fumagalli L; KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium., Vandoorne T; KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium., Baatsen P; VIB, Center for Brain & Disease Research, Research Group Molecular Neurobiology, Leuven, Belgium; KU Leuven - University of Leuven, VIB Bio Imaging Core, Leuven, Belgium., Kerstens A; VIB, Center for Brain & Disease Research, Research Group Molecular Neurobiology, Leuven, Belgium; KU Leuven - University of Leuven, VIB Bio Imaging Core, Leuven, Belgium., Giacomazzi G; KU Leuven - University of Leuven, Department of Development and Regeneration, Stem Cell and Developmental Biology, Leuven, Belgium., Pavie B; VIB, Center for Brain & Disease Research, Research Group Molecular Neurobiology, Leuven, Belgium; KU Leuven - University of Leuven, VIB Bio Imaging Core, Leuven, Belgium., Rossaert E; KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium., Beckers J; KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium., Sampaolesi M; KU Leuven - University of Leuven, Department of Development and Regeneration, Stem Cell and Developmental Biology, Leuven, Belgium., Van Damme P; KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium; University Hospitals Leuven, Department of Neurology, Leuven, Belgium., Van Den Bosch L; KU Leuven - University of Leuven, Department of Neurosciences, Experimental Neurology, and Leuven Brain Institute, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium. Electronic address: ludo.vandenbosch@kuleuven.be. |
المصدر: | Stem cell reports [Stem Cell Reports] 2021 Sep 14; Vol. 16 (9), pp. 2213-2227. Date of Electronic Publication: 2021 Apr 22. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 101611300 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-6711 (Electronic) Linking ISSN: 22136711 NLM ISO Abbreviation: Stem Cell Reports Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [Cambridge, MA] : Cell Press, c 2013- |
مواضيع طبية MeSH: | Lab-On-A-Chip Devices* , Mutation*, Histone Deacetylase 6/*antagonists & inhibitors , Histone Deacetylase Inhibitors/*pharmacology , Neuromuscular Junction/*genetics , Neuromuscular Junction/*physiopathology , RNA-Binding Protein FUS/*genetics, Agrin/metabolism ; Amyotrophic Lateral Sclerosis/etiology ; Amyotrophic Lateral Sclerosis/metabolism ; Amyotrophic Lateral Sclerosis/pathology ; Biomarkers ; Cell Culture Techniques ; Cell Differentiation/drug effects ; Coculture Techniques ; Fluorescent Antibody Technique ; Humans ; Induced Pluripotent Stem Cells/cytology ; Induced Pluripotent Stem Cells/metabolism ; Laminin/metabolism ; Microfluidic Analytical Techniques ; Motor Neurons/cytology ; Motor Neurons/drug effects ; Motor Neurons/metabolism ; Muscle Fibers, Skeletal/cytology ; Muscle Fibers, Skeletal/drug effects ; Muscle Fibers, Skeletal/metabolism ; Neuromuscular Junction/drug effects ; Neuronal Outgrowth/drug effects |
مستخلص: | Neuromuscular junctions (NMJs) ensure communication between motor neurons (MNs) and muscle; however, in MN disorders, such as amyotrophic lateral sclerosis (ALS), NMJs degenerate resulting in muscle atrophy. The aim of this study was to establish a versatile and reproducible in vitro model of a human motor unit to investigate the effects of ALS-causing mutations. Therefore, we generated a co-culture of human induced pluripotent stem cell (iPSC)-derived MNs and human primary mesoangioblast-derived myotubes in microfluidic devices. A chemotactic and volumetric gradient facilitated the growth of MN neurites through microgrooves resulting in the interaction with myotubes and the formation of NMJs. We observed that ALS-causing FUS mutations resulted in reduced neurite outgrowth as well as an impaired neurite regrowth upon axotomy. NMJ numbers were likewise reduced in the FUS-ALS model. Interestingly, the selective HDAC6 inhibitor, Tubastatin A, improved the neurite outgrowth, regrowth, and NMJ morphology, prompting HDAC6 inhibition as a potential therapeutic strategy for ALS. (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.) |
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فهرسة مساهمة: | Keywords: FUS; HDAC6; Tubastatin A; amyotrophic lateral sclerosis; microfluidic device; neurite outgrowth; neurite regrowth; neuromuscular junction |
المشرفين على المادة: | 0 (Agrin) 0 (Biomarkers) 0 (FUS protein, human) 0 (Histone Deacetylase Inhibitors) 0 (Laminin) 0 (RNA-Binding Protein FUS) EC 3.5.1.98 (HDAC6 protein, human) EC 3.5.1.98 (Histone Deacetylase 6) |
تواريخ الأحداث: | Date Created: 20210423 Date Completed: 20220309 Latest Revision: 20220309 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC8452598 |
DOI: | 10.1016/j.stemcr.2021.03.029 |
PMID: | 33891869 |
قاعدة البيانات: | MEDLINE |
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