Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination.
Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination.
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DOI：
10.1093/brain/awx012
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发表时间：
2017-04-01
期刊：
影响因子：
--
通讯作者：
Bennett DLH
中科院分区：
文献类型：
--
作者：
Clark AJ;Kaller MS;Galino J;Willison HJ;Rinaldi S;Bennett DLH
参见Saporta和Shy（doi：）对本文的科学评论。Clark等人报道，来源于iPSC的人感觉神经元可以通过培养的大鼠雪旺细胞形成髓鞘。这种共培养物以神经调节蛋白-1依赖性方式发展成熟有髓纤维的特征。与炎性周围神经病相关的抗神经节苷脂抗体既可阻碍髓鞘形成又可引起已形成的髓鞘的损失。参见Saporta和Shy（doi：）对本文的科学评论。轴突和雪旺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是必不可少的。我们已经建立了人诱导多能干细胞衍生的感觉神经元可以与大鼠雪旺细胞一起培养的条件，并首次与人神经元产生了长期稳定的髓鞘共培养物。这些培养物含有轴突与髓鞘形成的许旺细胞相互作用形成的专门结构域，例如Ranvier节点处的簇状电压门控钠通道和Shaker型钾通道（Kv1.2）。III型神经调节蛋白-1（TIIINRG1）在诱导多能干细胞衍生的感觉神经元中的表达强烈增强髓鞘形成，而相反，NRG1-ErbB通路的药理学阻断阻止髓鞘形成，为该通路促进人类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NRG 1所需的蛋白酶。由于BACE1也切割淀粉样前体蛋白，因此它是阿尔茨海默病的治疗靶点，然而，与其在NRG 1加工中的作用一致，我们发现BACE1抑制显著损害了我们的共培养系统中的髓鞘形成。为了利用共培养物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，包括来自具有感觉为主的炎性神经病的患者的抗体，所述炎性神经病具有混合的轴突和脱髓鞘电生理学。共培养物显示小鼠和人二唾液酸抗体都靶向结轴膜，在补体存在下诱导急性轴突变性，并损害髓鞘形成。人神经病相关IgM抗体也显示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的髓鞘形成共培养物提供了对轴突神经元信号传导的细胞和分子特化的见解，药理学试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。
See Saporta and Shy (doi:) for a scientific commentary on this article. Clark et al. report that human sensory neurons derived from iPSCs can be myelinated by rat Schwann cells in culture. Such co-cultures develop features of mature myelinated fibres in a neuregulin-1 dependent manner. Antiganglioside antibodies associated with inflammatory peripheral neuropathies can both impede myelination and cause loss of established myelin. See Saporta and Shy (doi:) 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.
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DOI：
10.1038/nrn.2016.46
发表时间：
2016-07
期刊：
Nature reviews. Neuroscience
影响因子：
--
作者：
Mertens J;Marchetto MC;Bardy C;Gage FH
通讯作者：
Gage FH
影响因子：
3.3
作者：
Boffey, J;Odaka, M;Willison, HJ
通讯作者：
Willison, HJ
影响因子：
2.5
作者：
Hitoshi, S;Kusunoki, S;Kanazawa, I
通讯作者：
Kanazawa, I
影响因子：
7.8
作者：
OWENS, GC;BOYD, CJ;SALZER, JL
通讯作者：
SALZER, JL
影响因子：
14.5
作者：
O'Hanlon, GM;Plomp, JJ;Willison, HJ
通讯作者：
Willison, HJ