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首页> 外文期刊>Journal of Cellular Physiology >Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes
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Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes

机译：溶酶体储存障碍对生物的影响间充质干细胞:证据从葡糖脑苷脂酶体外抑制(GBA)alpha-galactosidase (GLA)的酶

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摘要

Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues. Since the impairment of MSC functions could pose profound consequences on body physiology, we evaluated whether GBA and GLA silencing could affect the biology of MSCs isolated from bone marrow and amniotic fluid. Those cell populations were chosen given the former's key role in organ physiology and the latter's intriguing potential as an alternative stem cell model for human genetic disease. Our results revealed that GBA and GLA deficiencies prompted cell cycle arrest along with the impairment of autophagic flux and an increase of apoptotic and senescent cell percentages. Moreover, an increase in ataxia-telangiectasia-mutated staining 1hr after oxidative stress induction and a return to basal level at 48hr, along with persistent gamma-H2AX staining, indicated that MSCs properly activated DNA repair signaling, though some damages remained unrepaired. Our data therefore suggest that MSCs with reduced GBA or GLA activity are prone to apoptosis and senescence due to impaired autophagy and DNA repair capacity.
机译：溶酶体储存障碍(像)组成一个组罕见的多系统疾病导致的遗传基因突变,影响溶酶体体内平衡。疾病(GD)和Fabry疾病(FD)引起溶酶体的缺陷葡糖脑苷脂酶(GBA)和alpha-galactosidase(GLA)酶,分别。酶的缺乏,我们假设GD和FD患者的干细胞隔间也可能受到影响。间充质干细胞(msc)是常见的考虑到他们的作用调查人口造血作用和自我平衡的维护许多器官和组织。MSC函数可能会带来深远的影响人体生理学,我们评估是否GBA和杯子沉默可能影响的生物学msc从骨髓中分离和羊水。这些细胞群被选择了在器官生理学和前的关键作用后者的有趣的潜力作为替代人类遗传疾病的干细胞模型。结果显示,GBA和杯子缺乏引起细胞周期阻滞以及损伤的自噬流量和增加凋亡和衰老细胞百分比。此外,增加ataxia-telangiectasia-mutated染色后1小时氧化应激诱导和基底的回归水平在48小时,连同持久gamma-H2AX染色,表明msc正确激活DNA修复信号,尽管一些赔偿仍未修理的。msc与减少GBA或杯子活动容易因受损细胞凋亡与衰老自噬和DNA修复能力。

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