从人类诱导多能干细胞中提取的杜氏肌营养不良症骨骼肌细胞再现了各种钙失调途径

IF 4.3 2区 生物学 Q2 CELL BIOLOGY
Arnaud Delafenêtre , Charles-Albert Chapotte-Baldacci , Léa Dorémus , Emmanuelle Massouridès , Marianne Bernard , Matthieu Régnacq , Jérôme Piquereau , Aurélien Chatelier , Christian Cognard , Christian Pinset , Stéphane Sebille
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引用次数: 0

摘要

杜兴氏肌营养不良症(DMD)是一种 X 连锁进行性肌肉变性疾病,由肌营养不良蛋白基因突变引起,并导致过早死亡。作为一种主要的继发性疾病,肌营养不良症肌肉中细胞内钙浓度的异常升高导致了 DMD 的疾病进展。在本研究中,我们研究了从DMD患者体内生成的诱导多能干细胞衍生肌肉细胞(hiPSC-skMCs)调节细胞内钙浓度的特殊功能特征。与健康的hiPSC-skMCs相比,DMD hiPSC-skMCs显示出特定的自发钙信号,细胞内钙浓度水平较高。此外,与健康细胞相比,电场刺激或乙酰胆碱灌注可诱导 DMD hiPSC-skMCs 产生更高的钙反应。最后,Mn2+淬灭实验表明,与健康细胞相比,DMD hiPSC-skMCs 的组成型钙离子进入水平较高。我们的研究结果表明,DMD hiPSC-skMCs 表现出细胞内钙失调,这在其他几个模型中也得到了证实。通过对这些 DMD 细胞进行 RNAseq 分析,观察到的钙失调突显了一些机制,如自发和激活的肌质网(SR)释放或组成型钙离子进入,已知这些机制在其他肌营养不良模型中受到干扰。然而,在我们的 DMD hiPSC-skMCs 模型中,并没有发现储存操作的钙离子进入(SOCE)失调。这些结果表明,在其他动物模型中观察到的所有钙损伤机制在人类身上可能并不那么明显,而且可能会偏向于某些机制,而这些机制可能与 DMD 治疗的主要分子靶点相对应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Duchenne muscular dystrophy skeletal muscle cells derived from human induced pluripotent stem cells recapitulate various calcium dysregulation pathways

Duchenne muscular dystrophy skeletal muscle cells derived from human induced pluripotent stem cells recapitulate various calcium dysregulation pathways

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle degenerative disease, caused by mutations in the dystrophin gene and resulting in premature death. As a major secondary event, an abnormal elevation of the intracellular calcium concentration in the dystrophin-deficient muscle contributes to disease progression in DMD. In this study, we investigated the specific functional features of induced pluripotent stem cell-derived muscle cells (hiPSC-skMCs) generated from DMD patients to regulate intracellular calcium concentration. As compared to healthy hiPSC-skMCs, DMD hiPSC-skMCs displayed specific spontaneous calcium signatures with high levels of intracellular calcium concentration. Furthermore, stimulations with electrical field or with acetylcholine perfusion induced higher calcium response in DMD hiPSC-skMCs as compared to healthy cells. Finally, Mn2+ quenching experiments demonstrated high levels of constitutive calcium entries in DMD hiPSC-skMCs as compared to healthy cells. Our findings converge on the fact that DMD hiPSC-skMCs display intracellular calcium dysregulation as demonstrated in several other models. Observed calcium disorders associated with RNAseq analysis on these DMD cells highlighted some mechanisms, such as spontaneous and activated sarcoplasmic reticulum (SR) releases or constitutive calcium entries, known to be disturbed in other dystrophin-deficient models. However, store operated calcium entries (SOCEs) were not found to be dysregulated in our DMD hiPSC-skMCs model. These results suggest that all the mechanisms of calcium impairment observed in other animal models may not be as pronounced in humans and could point to a preference for certain mechanisms that could correspond to major molecular targets for DMD therapies.

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来源期刊
Cell calcium
Cell calcium 生物-细胞生物学
CiteScore
8.70
自引率
5.00%
发文量
115
审稿时长
35 days
期刊介绍: Cell Calcium covers the field of calcium metabolism and signalling in living systems, from aspects including inorganic chemistry, physiology, molecular biology and pathology. Topic themes include: Roles of calcium in regulating cellular events such as apoptosis, necrosis and organelle remodelling Influence of calcium regulation in affecting health and disease outcomes
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