细胞衍生基质力学作为胶原蛋白 VI 相关先天性肌肉萎缩症的功能读数

Tom White, Aristides Lopez-Marquez, Carmen Badosa, Cecilia Jimenez-Mallebrera, Josep Samitier, Marina I Giannotti, Anna Lagunas
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摘要

胶原蛋白 VI 相关先天性肌营养不良症(COL6-RDs)是由三个 COL6 基因中任何一个基因的致病变体引起的一系列神经肌肉疾病。该病的表型表现与遗传背景并不直接相关,临床表型重叠,从轻微的伯利姆肌病(BM)到严重的乌尔里希先天性肌营养不良症(UCMD)。诊断包括疾病的基因确认和基于最大运动能力的表型分类。开发能够识别表型特征的新工具可极大地促进 COL6-RD 的诊断和预后。COL6 基因突变会导致结缔组织细胞外基质(ECM)中的 COL6 缺乏或功能障碍,影响其纤维结构。我们的研究小组基于细胞衍生基质(CDMs)建立了个性化的 COL6-RD 临床前模型,可直接观察患者样本中 ECM 的纤维组织,并比较不同表型的特征。在此,我们使用基于原子力显微镜的力谱仪(AFM-FS)鉴定了患者 CDMs 的机械特性。我们观察到弹性模量(E)随表型而变化,并且与 CDMs 中的 COL6 组织相关。此外,我们还使用 AFM-FS 评估了来自基因编辑细胞的基质,结果发现与对照样本相比,E 值有所恢复。总之,这些结果预示着 CDMs 的机械分析有望成为一种补充性临床工具,提供有关 COL6-RD 及其对基因疗法反应的表型信息。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cell-derived matrices mechanics as a functional read-out in Collagen VI-related Congenital Muscular Dystrophies
Collagen VI-related congenital muscular dystrophies (COL6-RDs) are a set of neuromuscular conditions caused by pathogenic variants found in any of the three COL6 genes. The phenotypic expression of the disease does not directly correlate with the genetic background producing an overlapping spectrum of clinical phenotypes that goes from the mild Bethlem myopathy (BM) to the severe Ulrich congenital muscular dystrophy (UCMD). Diagnosis includes genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability. The development of new tools able to identify phenotype traits can significantly contribute to the diagnosis and prognosis of COL6-RDs. Mutations occurring in COL6 genes result in deficiency or dysfunction of COL6 incorporated into the extracellular matrix (ECM) of connective tissues, affecting its fibrillar structure. Our research group has established personalized pre-clinical models of COL6-RDs based on cell-derived matrices (CDMs), which allowed the direct observation of the fibrillar organization of the ECM in samples derived from patients, and to compare features amongst different phenotypes. Here, we have characterized the mechanical properties of CDMs from patients using atomic force microscopy-based force spectroscopy (AFM-FS). We observed that the elastic modulus (E) varies with the phenotype, and that it correlates with COL6 organization in the CDMs. We additionally used AFM-FS to evaluate matrices derived from genetically edited cells, which resulted in E value restoration compared to control samples. Altogether, these results anticipate the potential of mechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.
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