Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA; Linda Crnic Institute for Down Syndrome, Aurora, CO, 80045, USA.
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, 80045, USA.
Free Radic Biol Med. 2022 Jun;186:32-42. doi: 10.1016/j.freeradbiomed.2022.04.015. Epub 2022 May 7.
The ubiquity of cognitive deficits and early onset Alzheimer's disease in Down syndrome (DS) has focused much DS iPSC-based research on neuron degeneration and regeneration. Despite reports of elevated oxidative stress in DS brains, few studies assess the impact of this oxidative burden on iPSC differentiation. Here, we evaluate cellular specific redox differences in DS and euploid iPSCs and neural progenitor cells (NPCs) during critical intermediate stages of differentiation. Despite successful generation of NPCs, our results indicate accelerated neuroectodermal differentiation of DS iPSCs compared to isogenic, euploid controls. Specifically, DS embryoid bodies (EBs) and neural rosettes prematurely develop with distinct morphological differences from controls. Additionally, we observed developmental stage-specific alterations in mitochondrial superoxide production and SOD1/2 abundance, coupled with modulations in thioredoxin, thioredoxin reductase, and peroxiredoxin isoforms. Disruption of intracellular redox state and its associated signaling has the potential to disrupt cellular differentiation and development in DS lending to DS-specific phenotypes.
唐氏综合征（DS）患者普遍存在认知功能缺陷和早发性阿尔茨海默病，这使得基于 DS 诱导多能干细胞（iPSC）的研究主要集中在神经元变性和再生上。尽管有报道称 DS 大脑中的氧化应激水平升高，但很少有研究评估这种氧化应激对 iPSC 分化的影响。在这里，我们评估了在分化的关键中间阶段，DS 和整倍体 iPSC 及神经祖细胞（NPC）中的细胞特异性氧化还原差异。尽管成功生成了 NPC，但我们的结果表明，与同基因的整倍体对照相比，DS iPSC 的神经外胚层分化速度更快。具体来说，DS 类胚体（EBs）和神经玫瑰花结过早形成，与对照组具有明显的形态差异。此外，我们还观察到线粒体超氧阴离子产生和 SOD1/2 丰度的发育阶段特异性改变，同时伴随着硫氧还蛋白、硫氧还蛋白还原酶和过氧化物酶同工型的调节。细胞内氧化还原状态及其相关信号的破坏有可能扰乱 DS 中的细胞分化和发育，导致 DS 特异性表型。
