Mohammadnia Abdulshakour, Cui Qiao-Ling, Weng Chao, Yaqubi Moein, Fernandes Milton G F, Hall Jeffery A, Dudley Roy, Srour Myriam, Kennedy Timothy E, Stratton Jo Anne, Antel Jack P
Neuroimmunology Unit, Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montreal H3A 2B4, Canada.
Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Brain Commun. 2024 Mar 28;6(2):fcae109. doi: 10.1093/braincomms/fcae109. eCollection 2024.
Metformin restores the myelination potential of aged rat A2B5+ oligodendrocyte progenitor cells and may enhance recovery in children with post-radiation brain injury. Human late progenitor cells (O4+A2B5+) have a superior capacity to ensheath nanofibres compared to mature oligodendrocytes, with cells from paediatric sources exceeding adults. In this study, we assessed the effects of metformin on ensheathment capacity of human adult and paediatric progenitors and mature oligodendrocytes and related differences to transcriptional changes. A2B5+ progenitors and mature cells, derived from surgical tissues by immune-magnetic separation, were assessed for ensheathment capacity in nanofibre plates over 2 weeks. Metformin (10 µM every other day) was added to selected cultures. RNA was extracted from treated and control cultures after 2 days. For all ages, ensheathment by progenitors exceeded mature oligodendrocytes. Metformin enhanced ensheathment by adult donor cells but reduced ensheathment by paediatric cells. Metformin marginally increased cell death in paediatric progenitors. Metformin-induced changes in gene expression are distinct for each cell type. Adult progenitors showed up-regulation of pathways involved in the process of outgrowth and promoting lipid biosynthesis. Paediatric progenitors showed a relatively greater proportion of down- versus up-regulated pathways, these involved cell morphology, development and synaptic transmission. Metformin-induced AMP-activated protein kinase activation in all cell types; AMP-activated protein kinase inhibitor BML-275 reduced functional metformin effects only with adult cells. Our results indicate age and differentiation stage-related differences in human oligodendroglia lineage cells in response to metformin. Clinical trials for demyelinating conditions will indicate how these differences translate .
二甲双胍可恢复老年大鼠A2B5 +少突胶质前体细胞的髓鞘形成潜能，并可能增强放射性脑损伤儿童的恢复能力。与成熟少突胶质细胞相比，人类晚期前体细胞（O4 + A2B5 +）包裹纳米纤维的能力更强，其中来自儿科来源的细胞超过成人。在本研究中，我们评估了二甲双胍对人类成人和儿科前体细胞以及成熟少突胶质细胞包裹能力的影响，并将相关差异与转录变化联系起来。通过免疫磁珠分选从手术组织中分离出A2B5 +前体细胞和成熟细胞，在纳米纤维板上评估其2周内的包裹能力。将二甲双胍（每隔一天10 μM）添加到选定的培养物中。2天后从处理过的和对照培养物中提取RNA。对于所有年龄段，前体细胞的包裹能力均超过成熟少突胶质细胞。二甲双胍增强了成年供体细胞的包裹能力，但降低了儿科细胞的包裹能力。二甲双胍略微增加了儿科前体细胞的细胞死亡。二甲双胍诱导的基因表达变化在每种细胞类型中都是不同的。成年前体细胞显示出参与生长过程和促进脂质生物合成的途径上调。儿科前体细胞显示出下调与上调途径的比例相对较高，这些途径涉及细胞形态、发育和突触传递。二甲双胍在所有细胞类型中均诱导AMP激活的蛋白激酶活化；AMP激活的蛋白激酶抑制剂BML-275仅在成年细胞中降低了二甲双胍的功能作用。我们的结果表明，人类少突胶质谱系细胞在对二甲双胍的反应中存在与年龄和分化阶段相关的差异。脱髓鞘疾病的临床试验将表明这些差异如何转化。
