The Sidney and Judy Swartz Embryonic Stem Cell Research Center of The Goldyne Savad Institute of Gene Therapy & The Department of Obstetrics & Gynecology, Hadassah University Medical Center, Jerusalem 91120, Israel; Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada (IMRIC), Faculty of Medicine, The Hebrew University, P.O. Box 12272, 91120 Jerusalem, Israel.
The Sidney and Judy Swartz Embryonic Stem Cell Research Center of The Goldyne Savad Institute of Gene Therapy & The Department of Obstetrics & Gynecology, Hadassah University Medical Center, Jerusalem 91120, Israel.
EBioMedicine. 2019 Dec;50:274-289. doi: 10.1016/j.ebiom.2019.11.026. Epub 2019 Nov 29.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons (MNs). It was shown that human astrocytes with mutations in genes associated with ALS, like C9orf72 (C9) or SOD1, reduce survival of MNs. Astrocyte toxicity may be related to their dysfunction or the release of neurotoxic factors.
We used human induced pluripotent stem cell-derived astrocytes from ALS patients carrying C9orf72 mutations and non-affected donors. We utilized these cells to investigate astrocytic induced neuronal toxicity, changes in astrocyte transcription profile as well as changes in secretome profiles.
We report that C9-mutated astrocytes are toxic to MNs via soluble factors. The toxic effects of astrocytes are positively correlated with the length of astrocyte propagation in culture, consistent with the age-related nature of ALS. We show that C9-mutated astrocytes downregulate the secretion of several antioxidant proteins. In line with these findings, we show increased astrocytic oxidative stress and senescence. Importantly, media conditioned by C9-astrocytes increased oxidative stress in wild type MNs.
Our results suggest that dysfunction of C9-astrocytes leads to oxidative stress of themselves and MNs, which probably contributes to neurodegeneration. Our findings suggest that therapeutic strategies in familial ALS must not only target MNs but also focus on astrocytes to abrogate nervous system injury.
肌萎缩侧索硬化症（ALS）是一种进行性神经退行性疾病，影响运动神经元（MNs）。已经表明，携带与 ALS 相关基因突变的人类星形胶质细胞，如 C9orf72（C9）或 SOD1，会降低 MNs 的存活率。星形胶质细胞毒性可能与其功能障碍或释放神经毒性因子有关。
我们使用携带 C9orf72 突变和未受影响供体的 ALS 患者来源的人诱导多能干细胞衍生星形胶质细胞。我们利用这些细胞来研究星形胶质细胞诱导的神经元毒性、星形胶质细胞转录谱的变化以及分泌组谱的变化。
我们报告说 C9 突变星形胶质细胞通过可溶性因子对 MNs 有毒性。星形胶质细胞的毒性作用与星形胶质细胞在培养中的增殖长度呈正相关，与 ALS 的年龄相关性一致。我们表明 C9 突变星形胶质细胞下调几种抗氧化蛋白的分泌。与这些发现一致，我们显示出星形胶质细胞氧化应激和衰老增加。重要的是，C9 星形胶质细胞条件培养基增加了野生型 MNs 的氧化应激。
我们的结果表明 C9 星形胶质细胞的功能障碍导致自身和 MNs 的氧化应激，这可能导致神经退行性变。我们的研究结果表明，家族性 ALS 的治疗策略不仅必须针对 MNs，还必须集中在星形胶质细胞上，以消除神经系统损伤。
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