Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination

Clark, A. J., Kaller, M. S., Galino, J., Willison, H. J. , Rinaldi, S. and Bennett, D. L.H. (2017) Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination. Brain, 140(4), pp. 898-913. (doi: 10.1093/brain/awx012) (PMID:28334857) (PMCID:PMC5637940)

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Effective bidirectional signalling between axons and Schwann cells is essential for both the development and maintenance of peripheral nerve function. We have established conditions by which human induced pluripotent stem cell-derived sensory neurons can be cultured with rat Schwann cells, and have produced for the first time long-term and stable myelinating co-cultures with human neurons. These cultures contain the specialized domains formed by axonal interaction with myelinating Schwann cells, such as clustered voltage-gated sodium channels at the node of Ranvier and Shaker-type potassium channel (Kv1.2) at the juxtaparanode. Expression of type III neuregulin-1 (TIIINRG1) in induced pluripotent stem cell-derived sensory neurons strongly enhances myelination, while conversely pharmacological blockade of the NRG1-ErbB pathway prevents myelination, providing direct evidence for the ability of this pathway to promote the myelination of human sensory axons. The β-secretase, BACE1 is a protease needed to generate active NRG1 from the full-length form. Due to the fact that it also cleaves amyloid precursor protein, BACE1 is a therapeutic target in Alzheimer’s disease, however, consistent with its role in NRG1 processing we find that BACE1 inhibition significantly impairs myelination in our co-culture system. In order to exploit co-cultures to address other clinically relevant problems, they were exposed to anti-disialosyl ganglioside antibodies, including those derived from a patient with a sensory predominant, inflammatory neuropathy with mixed axonal and demyelinating electrophysiology. The co-cultures reveal that both mouse and human disialosyl antibodies target the nodal axolemma, induce acute axonal degeneration in the presence of complement, and impair myelination. The human, neuropathy-associated IgM antibody is also shown to induce complement-independent demyelination. Myelinating co-cultures using human induced pluripotent stem cell-derived sensory neurons thus provide insights into the cellular and molecular specialization of axoglial signalling, how pharmacological agents may promote or impede such signalling and the pathogenic effects of ganglioside antibodies.

Item Type:Articles
Keywords:Guillain-Barré syndrome, Schwann cell, chronic inflammatory demyelinating neuropathy, myelin, stem cells
Glasgow Author(s) Enlighten ID:Willison, Professor Hugh
Authors: Clark, A. J., Kaller, M. S., Galino, J., Willison, H. J., Rinaldi, S., and Bennett, D. L.H.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Brain
Publisher:Oxford University Press
ISSN (Online):1460-2156
Published Online:15 February 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Brain 140(4):898-913
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
544031The structural and functional diversity of anti-glycolipid antibody repertoires and their nerve binding domains in human autoimmune neuropathyHugh WillisonWellcome Trust (WELLCOME)092805/Z/10/ZIII -IMMUNOLOGY