Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics.
Patient-derived extracellular matrix demonstrates role of COL3A1 in blood vessel mechanics.
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DOI：
10.1016/j.actbio.2023.05.015
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发表时间：
2023-05
影响因子：
9.7
通讯作者：
Elizabeth L. Doherty;W. Y. Aw;Emily C. Warren;Max A Hockenberry;Chloe P. Whitworth;Grace Krohn;Stefanie Howell;B. Diekman;W. Legant;Hadi T. Nia;Anthony J. Hickey;W. Polacheck
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文献类型：
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作者：
Elizabeth L. Doherty;W. Y. Aw;Emily C. Warren;Max A Hockenberry;Chloe P. Whitworth;Grace Krohn;Stefanie Howell;B. Diekman;W. Legant;Hadi T. Nia;Anthony J. Hickey;W. Polacheck
血管Ehlers-Danlos综合征（vEDS）是一种罕见的常染色体显性遗传疾病，由COL 3A 1基因突变引起，使患者易患动脉瘤、动脉夹层和破裂。为了确定COL 3A 1变体在人动脉ECM的生物化学和生物物理特性中的作用，我们开发了一种直接从vEDS供体成纤维细胞合成ECM的方法。我们发现从vEDS供体成纤维细胞产生的ECM的蛋白质含量与来自健康供体的ECM显著不同，包括胶原亚型和与ECM结构完整性相关的其他蛋白质的上调。我们进一步发现，从具有甘氨酸取代突变的供体产生的ECM的特征在于增加的糖胺聚糖含量和独特的粘弹性机械性质，包括增加的应力松弛时间常数，导致人主动脉内皮细胞接种在ECM上时迁移速度降低。总的来说，这些结果表明，vEDS患者来源的成纤维细胞haringCOL 3A 1突变合成ECM的组成，结构和机械性能从健康供体不同。这些结果进一步表明，ECM的机械性能可以作为一个预后指标与vEDS患者，和由该方法提供的见解证明了更广泛的实用程序的细胞衍生的ECM在疾病modeling.Statement of SignificanceThe胶原蛋白III ECM力学的作用仍然不清楚，尽管报道的疾病，包括纤维化和癌症的作用。在这里，我们从血管性埃勒斯-丹洛斯综合征（vEDS）患者的原代供体细胞中产生纤维状、富含胶原蛋白的ECM，vEDS是一种由编码胶原蛋白III的基因突变引起的疾病。我们观察到从vEDS患者生长的ECM的特征在于独特的机械特征，包括改变的粘弹性。通过量化患者来源的ECM的结构、生物化学和机械特性，我们确定了vEDS的潜在药物靶点，同时更广泛地定义了胶原蛋白III在ECM力学中的作用。此外，ECM组装和力学中胶原蛋白III的结构/功能关系将为组织工程和再生医学的基质设计提供信息。
Vascular Ehlers-Danlos Syndrome (vEDS) is a rare autosomal dominant disease caused by mutations in theCOL3A1gene, which renders patients susceptible to aneurysm and arterial dissection and rupture. To determine the role ofCOL3A1variants in the biochemical and biophysical properties of human arterial ECM, we developed a method for synthesizing ECM directly from vEDS donor fibroblasts. We found that the protein content of the ECM generated from vEDS donor fibroblasts differed significantly from ECM from healthy donors, including upregulation of collagen subtypes and other proteins related to ECM structural integrity. We further found that ECM generated from a donor with a glycine substitution mutation was characterized by increased glycosaminoglycan content and unique viscoelastic mechanical properties, including increased time constant for stress relaxation, resulting in a decrease in migratory speed of human aortic endothelial cells when seeded on the ECM. Collectively, these results demonstrate that vEDS patient-derived fibroblasts harboringCOL3A1mutations synthesize ECM that differs in composition, structure, and mechanical properties from healthy donors. These results further suggest that ECM mechanical properties could serve as a prognostic indicator for patients with vEDS, and the insights provided by the approach demonstrate the broader utility of cell-derived ECM in disease modeling.Statement of SignificanceThe role of collagen III ECM mechanics remains unclear, despite reported roles in diseases including fibrosis and cancer. Here, we generate fibrous, collagen-rich ECM from primary donor cells from patients with vascular Ehlers-Danlos syndrome (vEDS), a disease caused by mutations in the gene that encodes collagen III. We observe that ECM grown from vEDS patients is characterized by unique mechanical signatures, including altered viscoelastic properties. By quantifying the structural, biochemical, and mechanical properties of patient-derived ECM, we identify potential drug targets for vEDS, while defining a role for collagen III in ECM mechanics more broadly. Furthermore, the structure/function relationships of collagen III in ECM assembly and mechanics will inform the design of substrates for tissue engineering and regenerative medicine.