title: Functional Connectivity under Optogenetic Control Allows Modeling of Human Neuromuscular Disease.
abstract: Capturing the full potential of human pluripotent stem cell (PSC)-derived neurons in disease modeling and regenerative medicine requires analysis in complex functional systems. Here we establish optogenetic control in human PSC-derived spinal motorneurons and show that co-culture of these cells with human myoblast-derived skeletal muscle builds a functional all-human neuromuscular junction that can be triggered to twitch upon light stimulation. To model neuromuscular disease we incubated these co-cultures with IgG from myasthenia gravis patients and active complement. Myasthenia gravis is an autoimmune disorder that selectively targets neuromuscular junctions. We saw a reversible reduction in the amplitude of muscle contractions, representing a surrogate marker for the characteristic loss of muscle strength seen in this disease. The ability to recapitulate key aspects of disease pathology and its symptomatic treatment suggests that this neuromuscular junction assay has significant potential for modeling of neuromuscular disease and regeneration.
authors.affiliation: The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA. Electronic address: just.msk@use.startmail.com.
authors.forename: Julius A
authors.initials: JA
authors.lastname: Steinbeck
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Jaiswal
authors.affiliation: The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Calder
authors.affiliation: The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kishinevsky
authors.affiliation: Department of Neurology, University of Wuerzburg, 97080 Wuerzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weishaupt
authors.affiliation: Department of Neurology, University of Wuerzburg, 97080 Wuerzburg, Germany.
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Toyka
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, USA; Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Goldstein
authors.affiliation: The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065, USA. Electronic address: studerl@mskcc.org.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Studer
mesh_terms: D015551:Autoimmunity; D018920:Coculture Techniques; D003165:Complement System Proteins; D053595:Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry; D007150:Immunohistochemistry; D008027:Light; D009046:Motor Neurons / Q000473:pathology*; D018482:Muscle, Skeletal / Q000502:physiology; D009132:Muscles / Q000502:physiology; D009157:Myasthenia Gravis / Q000276:immunology* / Q000503:physiopathology; D032446:Myoblasts / Q000166:cytology; D009468:Neuromuscular Diseases / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000503:physiopathology*; D062308:Optogenetics / Q000379:methods*; D039904:Pluripotent Stem Cells / Q000166:cytology; D012038:Regeneration; D013116:Spinal Cord / Q000473:pathology; D016704:Synapsins / Q000378:metabolism / Q000502:physiology
chemical_list: D007074:Immunoglobulin G; D016704:Synapsins; D003165:Complement System Proteins