Fernandes Milton Guilherme Forestieri, Luo Julia Xiao Xuan, Cui Qiao-Ling, Perlman Kelly, Pernin Florian, Yaqubi Moein, Hall Jeffery A, Dudley Roy, Srour Myriam, Couturier Charles P, Petrecca Kevin, Larochelle Catherine, Healy Luke M, Stratton Jo Anne, Kennedy Timothy E, Antel Jack P
Neuroimmunology Unit, Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, QC, H3A 2B4, Canada.
Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Verdun, QC, H4H 1R3, Canada.
Commun Biol. 2021 Jan 4;4(1):20. doi: 10.1038/s42003-020-01557-1.
Myelin destruction and oligodendrocyte (OL) death consequent to metabolic stress is a feature of CNS disorders across the age spectrum. Using cells derived from surgically resected tissue, we demonstrate that young (<age 5) pediatric-aged sample OLs are more resistant to in-vitro metabolic injury than fetal O4+ progenitor cells, but more susceptible to cell death and apoptosis than adult-derived OLs. Pediatric but not adult OLs show measurable levels of TUNEL+ cells, a feature of the fetal cell response. The ratio of anti- vs pro-apoptotic BCL-2 family genes are increased in adult vs pediatric (<age 5) mature OLs and in more mature OL lineage cells. Lysosomal gene expression was increased in adult and pediatric compared to fetal OL lineage cells. Cell death of OLs was increased by inhibiting pro-apoptotic BCL-2 gene and autophagy activity. These distinct age-related injury responses should be considered in designing therapies aimed at reducing myelin injury.
代谢应激导致的髓鞘破坏和少突胶质细胞（OL）死亡是各年龄段中枢神经系统疾病的一个特征。利用手术切除组织来源的细胞，我们证明，年幼（5岁以下）儿童期样本中的OL比胎儿O4 +祖细胞对体外代谢损伤更具抗性，但比成人来源的OL更容易发生细胞死亡和凋亡。儿童而非成人的OL显示出可测量水平的TUNEL +细胞，这是胎儿细胞反应的一个特征。抗凋亡与促凋亡BCL-2家族基因的比例在成人与儿童（5岁以下）成熟OL以及更成熟的OL谱系细胞中增加。与胎儿OL谱系细胞相比，成人和儿童的溶酶体基因表达增加。抑制促凋亡BCL-2基因和自噬活性会增加OL的细胞死亡。在设计旨在减少髓鞘损伤的治疗方法时，应考虑这些与年龄相关的不同损伤反应。
