Neurodegenerative disorders share the final degenerative pathway, the inflammation-induced apoptosis and/or necrosis, irrespective of their etiology, be it of acute and chronic traumatic, vascular and idiopathic origin. Although disease-modifying strategies are an unmet need in these disorders, lately, (pre)clinical studies suggested favorable effects after an intervention with bone marrow-derived stromal cells (bm-SC). Recent interventions with intrathecal transplantation of these cells in preclinical rodent models improved the functional outcome and reduced the inflammation, but not anti-inflammatory drugs. The benefit of bm-SCs was demonstrated in rats with an acute (traumatic spinal cord injury, tSCI) and in mice with a chronic [amyotrophic lateral sclerosis (ALS)-like FUS 1-358 or SOD1-G93-A mutation] neurodegenerative process. Bm-SCs, were found to modify underlying disease processes, to reduce final clinical SCI-related outcome, and to slow down ALS-like clinical progression. After double-blind interventions with bm-SC transplantations, Vehicle (placebo), and (non)steroidal anti-inflammatory drugs (Methylprednisolone, Riluzole, Celecoxib), clinical, histological and histochemical findings, serum/spinal cytokines, markers for spinal microglial activation inclusive, evidenced the cell-to-cell action of bm-SCs in both otherwise healthy and immune-deficient tSCI-rats, as well as wild-type and FUS/SOD1-transgenic ALS-like mice. The multi-pathway hypothesis of the cell-to-cell action of bmSCs, presumably using extracellular vesicles (EVs) as carriers of messages in the form of RNAs, DNA, proteins, and lipids rather than influencing a single inflammatory pathway, could be justified by the reported differences of cytokines and other chemokines in the serum and spinal tissue. The mode of action of bm-SCs is hypothesized to be associated with its dedicated adjustment of the pro-apoptotic glycogen synthase kinase-3β level towards an anti-apoptotic level whereas their multi-pathway hypothesis seems to be confirmed by the decreased levels of the pro-inflammatory interleukin (IL)-1β and tumor necrosis factor (TNF) as well as the level of the marker of activated microglia, ionized calcium binding adapter (Iba)-1 level.

中文翻译：

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为什么骨髓基质细胞的抗炎信号能改善抗炎药失效的神经退行性疾病？

神经退行性疾病具有最终的退行性途径，即由炎症引起的凋亡和/或坏死，无论其病因如何，无论是急性和慢性创伤，血管和特发性起源。尽管在这些疾病中尚无缓解疾病的策略，但最近，（临床前）临床研究表明，在对骨髓源性基质细胞（bm-SC）进行干预后，效果良好。在临床前的啮齿动物模型中对这些细胞进行鞘内移植的最新干预措施改善了功能结局并减少了炎症，但没有消炎药。在患有急性（创伤性脊髓损伤，tSCI）的大鼠和患有慢性[肌萎缩性侧索硬化症（ALS）的FUS 1-358或SOD1-G93-A突变]神经变性过程的小鼠中证明了bm-SCs的益处。Bm-SC，被发现可以改变潜在的疾病过程，减少最终的临床SCI相关结局，并减慢ALS样的临床进展。在对bm-SC移植，媒介物（安慰剂）和（非）类固醇消炎药（甲基强的松龙，利鲁唑，塞来昔布）进行双盲干预后，临床，组织学和组织化学结果，血清/脊髓细胞因子，脊髓小胶质细胞活化标记包括在内，证明了在健康和免疫缺陷的tSCI大鼠以及野生型和FUS / SOD1转基因ALS样小鼠中bm-SC的细胞间作用。bmSCs的细胞间作用的多途径假设，大概是使用细胞外小泡（EV）作为RNA，DNA，蛋白质和脂质形式的信息载体，而不是影响单个炎症途径，据报道血清和脊髓组织中细胞因子和其他趋化因子的差异可以证明这一点是合理的。据推测，bm-SCs的作用方式与其将促凋亡糖原合酶激酶-3β的水平专门调节至抗凋亡水平有关，而其多途径假说似乎已被bm-SCs的水平降低所证实。促炎性白介素（IL）-1β和肿瘤坏死因子（TNF）以及活化的小胶质细胞的标志物水平，离子钙结合衔接子（Iba）-1水平。