Clark Alex J, Kaller Malte S, Galino Jorge, Willison Hugh J, Rinaldi Simon, Bennett David L H
Nuffield Department of Clinical Neurosciences, West Wing, John Radcliffe Hospital, Oxford, UK.
Neuroimmunology Group, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK.
Brain. 2017 Apr 1;140(4):898-913. doi: 10.1093/brain/awx012.
See Saporta and Shy (doi:10.1093/awx048) for a scientific commentary on this article.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.awx012media15372351982001.
有关本文的科学评论，请参阅萨波塔和施伊（doi:10.1093/awx048）。轴突与施万细胞之间有效的双向信号传导对于周围神经功能的发育和维持至关重要。我们已经建立了将人诱导多能干细胞衍生的感觉神经元与大鼠施万细胞共培养的条件，并首次建立了与人神经元长期稳定的髓鞘形成共培养体系。这些培养物包含轴突与髓鞘形成施万细胞相互作用形成的特化区域，如郎飞结处聚集的电压门控钠通道和近结旁的Shaker型钾通道（Kv1.2）。诱导多能干细胞衍生的感觉神经元中III型神经调节蛋白-1（TIIINRG1）的表达强烈增强髓鞘形成，而相反，NRG1-ErbB途径的药理学阻断则阻止髓鞘形成，为该途径促进人感觉轴突髓鞘形成的能力提供了直接证据。β-分泌酶BACE1是从全长形式产生活性NRG1所需的蛋白酶。由于它还切割淀粉样前体蛋白，BACE1是阿尔茨海默病中的一个治疗靶点，然而，与其在NRG1加工中的作用一致，我们发现BACE1抑制在我们的共培养系统中显著损害髓鞘形成。为了利用共培养来解决其他临床相关问题，将它们暴露于抗二唾液酸神经节苷脂抗体中，包括那些来自患有感觉为主、炎症性神经病变且伴有混合性轴突和脱髓鞘电生理的患者的抗体。共培养表明小鼠和人二唾液酸抗体均靶向结处轴膜，在补体存在下诱导急性轴突变性，并损害髓鞘形成。人神经病变相关IgM抗体也被证明可诱导补体非依赖性脱髓鞘。因此，使用人诱导多能干细胞衍生的感觉神经元进行的髓鞘形成共培养为轴突-神经胶质信号传导的细胞和分子特化、药物制剂如何促进或阻碍这种信号传导以及神经节苷脂抗体的致病作用提供了见解。awx012media15372351982001
