Aberrant cerebellar Purkinje cell function repaired in vivo by fusion with infiltrating bone marrow-derived cells.
Aberrant cerebellar Purkinje cell function repaired in vivo by fusion with infiltrating bone marrow-derived cells.
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DOI：
10.1007/s00401-018-1833-z
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发表时间：
2018-06
影响因子：
12.7
通讯作者：
Wilkins A
中科院分区：
文献类型：
--
作者：
Kemp KC;Dey R;Verhagen J;Scolding NJ;Usowicz MM;Wilkins A
众所周知，骨髓来源的细胞可以渗透到成人的大脑中，并与小脑浦肯野细胞融合。组织学观察表明，这种异型细胞融合事件在小脑损伤后明显更频繁，这表明它们可能在保护成熟的脑神经元方面发挥作用。到目前为止，细胞融合可以保存或恢复成年脑神经元的结构和功能的可能性还没有被直接讨论；事实上，尽管经常有人提出，受益的可能性一直是相当猜测的。在这里，我们首次报道了在体内，在成熟的大脑中，骨髓来源的细胞与神经元融合，导致形成自发放电的神经元。值得注意的是，我们还提供了证据，支持异型细胞融合作为修复浦肯野细胞结构和电生理学的病理变化的生物学机制的概念。我们在表达增强型绿色荧光蛋白标记的骨髓细胞的嵌合小鼠中诱导了慢性中枢神经系统炎症。随后的深入组织学分析显示浦肯野细胞有明显的损伤。此外，骨髓来源的细胞和浦肯野细胞之间的细胞融合发生率增加，表现为增强的表达绿色荧光蛋白的双核异核体。这些融合细胞在形态、胞体大小、合成神经递质γ-氨基丁酸的能力以及来自邻近细胞的突触神经支配方面与健康的浦肯野细胞相似。体外自发放电的细胞外记录显示，在小脑炎症的背景下，非融合浦肯野细胞的主要放电模式发生了转变。相比之下，融合的浦肯野细胞的放电模式与健康对照小脑相同，表明骨髓来源的细胞与浦肯野细胞的融合减轻了细胞损伤对电活动的影响。总之，我们的组织学和电生理学结果为成年生活中神经细胞受到保护的生理过程提供了新的基本见解。本文的在线版本(10.1007/s00401181833-z)包含补充材料，授权用户可以使用。
Bone marrow-derived cells are known to infiltrate the adult brain and fuse with cerebellar Purkinje cells. Histological observations that such heterotypic cell fusion events are substantially more frequent following cerebellar injury suggest they could have a role in the protection of mature brain neurons. To date, the possibility that cell fusion can preserve or restore the structure and function of adult brain neurons has not been directly addressed; indeed, though frequently suggested, the possibility of benefit has always been rather speculative. Here we report, for the first time, that fusion of a bone marrow-derived cell with a neuron in vivo, in the mature brain, results in the formation of a spontaneously firing neuron. Notably, we also provide evidence supporting the concept that heterotypic cell fusion acts as a biological mechanism to repair pathological changes in Purkinje cell structure and electrophysiology. We induced chronic central nervous system inflammation in chimeric mice expressing bone marrow cells tagged with enhanced green fluorescent protein. Subsequent in-depth histological analysis revealed significant Purkinje cell injury. In addition, there was an increased incidence of cell fusion between bone marrow-derived cells and Purkinje cells, revealed as enhanced green fluorescent protein-expressing binucleate heterokaryons. These fused cells resembled healthy Purkinje cells in their morphology, soma size, ability to synthesize the neurotransmitter gamma-aminobutyric acid, and synaptic innervation from neighbouring cells. Extracellular recording of spontaneous firing ex vivo revealed a shift in the predominant mode of firing of non-fused Purkinje cells in the context of cerebellar inflammation. By contrast, the firing patterns of fused Purkinje cells were the same as in healthy control cerebellum, indicating that fusion of bone marrow-derived cells with Purkinje cells mitigated the effects of cell injury on electrical activity. Together, our histological and electrophysiological results provide novel fundamental insights into physiological processes by which nerve cells are protected in adult life. The online version of this article (10.1007/s00401-018-1833-z) contains supplementary material, which is available to authorized users.
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影响因子：
7.1
作者：
Caporali P;Bruno F;Palladino G;Dragotto J;Petrosini L;Mangia F;Erickson RP;Canterini S;Fiorenza MT
通讯作者：
Fiorenza MT
影响因子：
12.7
作者：
Kemp K;Wilkins A;Scolding N
通讯作者：
Scolding N
影响因子：
64.8
作者：
Alvarez-Dolado, M;Pardal, R;Alvarez-Buylla, A
通讯作者：
Alvarez-Buylla, A
影响因子：
6.4
作者：
Kutzelnigg, Alexandra;Faber-Rod, Jens C.;Lassmann, Hans
通讯作者：
Lassmann, Hans
影响因子：
29
作者：
Arino, Helena;Gresa-Arribas, Nuria;Graus, Francesc
通讯作者：
Graus, Francesc