TNFα可防止FGF4介导的人类ALS模型中星形胶质细胞功能障碍和反应性的拯救
TNFα prevents FGF4-mediated rescue of astrocyte dysfunction and reactivity in human ALS models
影响因子:5.60000
分区:医学2区 Top / 神经科学2区
发表日期:2024 Oct 15
作者:
Erika Velasquez, Ekaterina Savchenko, Sara Marmolejo-Martínez-Artesero, Désiré Challuau, Aline Aebi, Yuriy Pomeshchik, Nuno Jorge Lamas, Mauno Vihinen, Melinda Rezeli, Bernard Schneider, Cedric Raoul, Laurent Roybon
摘要
星形胶质细胞在肌萎缩性侧面硬化症（ALS）的发作和进展中起着至关重要的作用，这是一种致命的致命疾病，标志着中枢神经系统中运动神经元（MN）的变性。尽管已知ALS中的星形胶质细胞对MN有毒，但导致其神经毒性表型的病理变化仍然很少了解。在这项研究中，我们从诱导的多能干细胞（IPSC）中产生了人类星形胶质细胞，这些干细胞（IPSC）携带了ALS相关的A4V突变，在超氧化物歧化酶1（SOD1）中检查以检查早期的细胞途径和网络变化。蛋白质组学分析表明，与对照星形细胞相比，ALS星形胶质细胞既功能障碍又反应性。我们确定了与ALS病理学和先天免疫CGAS刺激途径相关的蛋白质水平的重大变化。此外，我们发现ALS星形胶质细胞反应性不同于用肿瘤坏死因子α（TNFα）处理的对照星形胶质细胞，这是炎症反应中的关键细胞因子。然后，我们评估了成纤维细胞生长因子（FGF）2、4、16和18的潜力，以逆转ALS星形胶质细胞表型。其中，FGF4在体外成功逆转了ALS星形胶质细胞功能障碍和反应性。当递送到ALS的SOD1G93A小鼠模型的脊髓时，FGF4降低了星形胶质细胞反应性。但是，这不足以保护MN免受细胞死亡。进一步的分析表明，TNFα废除了FGF4实现的反应性降低，这表明FGF4完全拯救了ALS表型，这受到了体内持续的复杂神经炎症过程的阻碍。总而言之，我们的数据表明，由ALS IPSC产生的星形胶质细胞本质上是功能失调，并且表现出免疫反应性表型。有效靶向体内星形胶质细胞功能障碍和反应性可能有助于减轻ALS并预防MN死亡。
Abstract
Astrocytes play a crucial role in the onset and progression of amyotrophic lateral sclerosis (ALS), a fatal disorder marked by the degeneration of motor neurons (MNs) in the central nervous system. Although astrocytes in ALS are known to be toxic to MNs, the pathological changes leading to their neurotoxic phenotype remain poorly understood. In this study, we generated human astrocytes from induced pluripotent stem cells (iPSCs) carrying the ALS-associated A4V mutation in superoxide dismutase 1 (SOD1) to examine early cellular pathways and network changes. Proteomic analysis revealed that ALS astrocytes are both dysfunctional and reactive compared to control astrocytes. We identified significant alterations in the levels of proteins linked to ALS pathology and the innate immune cGAS-STING pathway. Furthermore, we found that ALS astrocyte reactivity differs from that of control astrocytes treated with tumor necrosis factor alpha (TNFα), a key cytokine in inflammatory reactions. We then evaluated the potential of fibroblast growth factor (FGF) 2, 4, 16, and 18 to reverse ALS astrocyte phenotype. Among these, FGF4 successfully reversed ALS astrocyte dysfunction and reactivity in vitro. When delivered to the spinal cord of the SOD1G93A mouse model of ALS, FGF4 lowered astrocyte reactivity. However, this was not sufficient to protect MNs from cell death. Further analysis indicated that TNFα abrogated the reactivity reduction achieved by FGF4, suggesting that complete rescue of the ALS phenotype by FGF4 is hindered by ongoing complex neuroinflammatory processes in vivo. In summary, our data demonstrate that astrocytes generated from ALS iPSCs are inherently dysfunctional and exhibit an immune reactive phenotype. Effectively targeting astrocyte dysfunction and reactivity in vivo may help mitigate ALS and prevent MN death.