Luchetti Andrea, Ciafrè Silvia Anna, Murdocca Michela, Malgieri Arianna, Masotti Andrea, Sanchez Massimo, Farace Maria Giulia, Novelli Giuseppe, Sangiuolo Federica
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Gene Expression-Microarrays Laboratory, Bambino Gesù Children's Hospital-IRCCS Polo di Ricerca-V.le di San Paolo 15, 00146 Rome, Italy.
Int J Mol Sci. 2015 Aug 6;16(8):18312-27. doi: 10.3390/ijms160818312.
Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder and the leading genetic cause of death in infants. Despite the disease-causing gene, survival motor neuron (SMN1), encodes a ubiquitous protein, SMN1 deficiency preferentially affects spinal motor neurons (MNs), leaving the basis of this selective cell damage still unexplained. As neural stem cells (NSCs) are multipotent self-renewing cells that can differentiate into neurons, they represent an in vitro model for elucidating the pathogenetic mechanism of neurodegenerative diseases such as SMA. Here we characterize for the first time neural stem cells (NSCs) derived from embryonic spinal cords of a severe SMNΔ7 SMA mouse model. SMNΔ7 NSCs behave as their wild type (WT) counterparts, when we consider neurosphere formation ability and the expression levels of specific regional and self-renewal markers. However, they show a perturbed cell cycle phase distribution and an increased proliferation rate compared to wild type cells. Moreover, SMNΔ7 NSCs are characterized by the differential expression of a limited number of miRNAs, among which miR-335-5p and miR-100-5p, reduced in SMNΔ7 NSCs compared to WT cells. We suggest that such miRNAs may be related to the proliferation differences characterizing SMNΔ7 NSCs, and may be potentially involved in the molecular mechanisms of SMA.
脊髓性肌萎缩症（SMA）是一种遗传性神经肌肉疾病，是婴儿死亡的主要遗传原因。尽管致病基因生存运动神经元（SMN1）编码一种普遍存在的蛋白质，但SMN1缺乏会优先影响脊髓运动神经元（MNs），这种选择性细胞损伤的基础仍未得到解释。由于神经干细胞（NSCs）是多能自我更新细胞，可分化为神经元，它们代表了一种体外模型，用于阐明诸如SMA等神经退行性疾病的发病机制。在这里，我们首次对源自严重SMNΔ7 SMA小鼠模型胚胎脊髓的神经干细胞（NSCs）进行了表征。当我们考虑神经球形成能力以及特定区域和自我更新标志物的表达水平时，SMNΔ7神经干细胞的行为与其野生型（WT）对应物相同。然而，与野生型细胞相比，它们显示出细胞周期阶段分布紊乱和增殖率增加。此外，SMNΔ7神经干细胞的特征是有限数量的miRNA的差异表达，其中与WT细胞相比，SMNΔ7神经干细胞中的miR-335-5p和miR-100-5p减少。我们认为这些miRNA可能与表征SMNΔ7神经干细胞的增殖差异有关，并且可能潜在地参与SMA的分子机制。
