Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA.
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Aging (Albany NY). 2020 Jul 8;12(14):15134-15156. doi: 10.18632/aging.103612.
Multiple sclerosis (MS) is a central nervous system inflammatory demyelinating disease and the most common cause of non-traumatic disability in young adults. Despite progress in the treatment of the active relapsing disease, therapeutic options targeting irreversible progressive decline remain limited. Studies using skin fibroblasts derived from patients with neurodegenerative disorders demonstrate that cell stress pathways and bioenergetics are altered when compared to healthy individuals. However, findings in MS skin fibroblasts are limited. Here, we collected skin fibroblasts from 24 healthy control individuals, 30 patients with MS, and ten with amyotrophic lateral sclerosis (ALS) to investigate altered cell stress profiles. We observed endoplasmic reticulum swelling in MS skin fibroblasts, and increased gene expression of cell stress markers including , , , , , and . When challenged against hydrogen peroxide, MS skin fibroblasts had reduced resiliency compared to ALS and controls. Mitochondrial and glycolytic functions were perturbed in MS skin fibroblasts while exhibiting a significant increase in lactate production over ALS and controls. Our results suggest that MS skin fibroblasts have an underlying stress phenotype, which may be disease specific. Interrogating MS skin fibroblasts may provide patient specific molecular insights and aid in prognosis, diagnosis, and therapeutic testing enhancing individualized medicine.
多发性硬化症（MS）是一种中枢神经系统炎症性脱髓鞘疾病，也是年轻人非创伤性残疾的最常见原因。尽管在治疗活动性复发疾病方面取得了进展，但针对不可逆转的进行性衰退的治疗选择仍然有限。使用源自神经退行性疾病患者的皮肤成纤维细胞进行的研究表明，与健康个体相比，细胞应激途径和生物能量发生了改变。然而，MS 皮肤成纤维细胞的研究结果有限。在这里，我们收集了 24 名健康对照个体、30 名 MS 患者和 10 名肌萎缩侧索硬化症（ALS）患者的皮肤成纤维细胞，以研究改变的细胞应激谱。我们观察到 MS 皮肤成纤维细胞内质网肿胀，并观察到细胞应激标志物的基因表达增加，包括 、 、 、 、 和 。与 ALS 和对照组相比，MS 皮肤成纤维细胞在过氧化氢挑战下的弹性降低。MS 皮肤成纤维细胞的线粒体和糖酵解功能受到干扰，同时与 ALS 和对照组相比，乳酸产量显著增加。我们的结果表明，MS 皮肤成纤维细胞具有潜在的应激表型，这可能是疾病特异性的。研究 MS 皮肤成纤维细胞可能为患者提供特定的分子见解，并有助于预后、诊断和治疗测试，增强个体化医疗。
