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Article: Optogenetic modeling of human neuromuscular circuits in Duchenne muscular dystrophy with CRISPR and pharmacological corrections

TitleOptogenetic modeling of human neuromuscular circuits in Duchenne muscular dystrophy with CRISPR and pharmacological corrections
Authors
Issue Date2021
PublisherAmerican Association for the Advancement of Science: Science Advances. The Journal's web site is located at http://www.scienceadvances.org/
Citation
Science Advances, 2021, v. 7 n. 37, p. article no. eabi8787 How to Cite?
AbstractDuchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations leading to skeletal muscle weakness and wasting. Dystrophin is enriched at the neuromuscular junction (NMJ), but how NMJ abnormalities contribute to DMD pathogenesis remains unclear. Here, we combine transcriptome analysis and modeling of DMD patient-derived neuromuscular circuits with CRISPR-corrected isogenic controls in compartmentalized microdevices. We show that NMJ volumes and optogenetic motor neuron–stimulated myofiber contraction are compromised in DMD neuromuscular circuits, which can be rescued by pharmacological inhibition of TGFβ signaling, an observation validated in a 96-well human neuromuscular circuit coculture assay. These beneficial effects are associated with normalization of dysregulated gene expression in DMD myogenic transcriptomes affecting NMJ assembly (e.g., MUSK) and axon guidance (e.g., SLIT2 and SLIT3). Our study provides a new human microphysiological model for investigating NMJ defects in DMD and assessing candidate drugs and suggests that enhancing neuromuscular connectivity may be an effective therapeutic strategy.
Persistent Identifierhttp://hdl.handle.net/10722/306278
ISSN
2023 Impact Factor: 11.7
2023 SCImago Journal Rankings: 4.483
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorParedes-Redondo, A-
dc.contributor.authorHarley, P-
dc.contributor.authorManiati, E-
dc.contributor.authorRyan, D-
dc.contributor.authorLouzada, S-
dc.contributor.authorMeng, J-
dc.contributor.authorKowala, A-
dc.contributor.authorFu, B-
dc.contributor.authorYang, F-
dc.contributor.authorLiu, P-
dc.contributor.authorMarino, S-
dc.contributor.authorPourquié, O-
dc.contributor.authorMuntoni, F-
dc.contributor.authorWang, J-
dc.contributor.authorLieberam, I-
dc.contributor.authorLin, YY-
dc.date.accessioned2021-10-20T10:21:20Z-
dc.date.available2021-10-20T10:21:20Z-
dc.date.issued2021-
dc.identifier.citationScience Advances, 2021, v. 7 n. 37, p. article no. eabi8787-
dc.identifier.issn2375-2548-
dc.identifier.urihttp://hdl.handle.net/10722/306278-
dc.description.abstractDuchenne muscular dystrophy (DMD) is caused by dystrophin gene mutations leading to skeletal muscle weakness and wasting. Dystrophin is enriched at the neuromuscular junction (NMJ), but how NMJ abnormalities contribute to DMD pathogenesis remains unclear. Here, we combine transcriptome analysis and modeling of DMD patient-derived neuromuscular circuits with CRISPR-corrected isogenic controls in compartmentalized microdevices. We show that NMJ volumes and optogenetic motor neuron–stimulated myofiber contraction are compromised in DMD neuromuscular circuits, which can be rescued by pharmacological inhibition of TGFβ signaling, an observation validated in a 96-well human neuromuscular circuit coculture assay. These beneficial effects are associated with normalization of dysregulated gene expression in DMD myogenic transcriptomes affecting NMJ assembly (e.g., MUSK) and axon guidance (e.g., SLIT2 and SLIT3). Our study provides a new human microphysiological model for investigating NMJ defects in DMD and assessing candidate drugs and suggests that enhancing neuromuscular connectivity may be an effective therapeutic strategy.-
dc.languageeng-
dc.publisherAmerican Association for the Advancement of Science: Science Advances. The Journal's web site is located at http://www.scienceadvances.org/-
dc.relation.ispartofScience Advances-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleOptogenetic modeling of human neuromuscular circuits in Duchenne muscular dystrophy with CRISPR and pharmacological corrections-
dc.typeArticle-
dc.identifier.emailLiu, P: pliu88@hku.hk-
dc.identifier.authorityLiu, P=rp02328-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1126/sciadv.abi8787-
dc.identifier.pmid34516770-
dc.identifier.pmcidPMC8442926-
dc.identifier.scopuseid_2-s2.0-85114782594-
dc.identifier.hkuros327323-
dc.identifier.volume7-
dc.identifier.issue37-
dc.identifier.spagearticle no. eabi8787-
dc.identifier.epagearticle no. eabi8787-
dc.identifier.isiWOS:000695713400011-
dc.publisher.placeUnited States-

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