Transthyretin alters cardiac fibroblast structure, function and inflammatory gene expression.

Age-related wild type transthyretin amyloidosis (wtATTR) is characterized by systemic deposition of amyloidogenic fibrils of misfolded transthyretin (TTR) in the connective tissue of many organs. In the heart this leads to cardiac dysfunction, which is a significant cause of age-related heart failure. The hypothesis tested is that TTR affects cardiac fibroblasts in ways that may contribute to fibrosis. When primary cardiac fibroblasts were cultured on TTR-deposited substrates, the F-actin cytoskeleton disorganized, focal adhesion formation decreased, and nuclear shape was flattened. Fibroblasts had faster collective and single cell migration velocities on TTR-deposited substrates. Additionally, fibroblasts cultured on microposts with TTR deposition had reduced attachment and increased proliferation above untreated. Transcriptomic and proteomic analyses of fibroblasts grown on glass covered with TTR showed significant upregulation of inflammatory genes after 48 hours, indicative of progression in TTR-based diseases. Together, results suggest that TTR deposited in tissue extracellular matrix may affect both the structure, function and gene expression of cardiac fibroblasts. As therapies for wtATTR are cost-prohibitive and only slow disease progression, better understanding of cellular maladaptation may elucidate novel therapeutic targets.年龄相关性野生型转甲状腺素蛋白淀粉样变性（wtATTR）以错误折叠的转甲状腺素蛋白（TTR）形成的淀粉样原纤维在全身多处器官结缔组织中系统性沉积为特征。当病变累及心脏时，会引发心功能障碍，这是年龄相关性心力衰竭的重要诱因之一。本研究验证的假说为：TTR可通过特定途径影响心脏成纤维细胞，进而可能促进纤维化进程。实验中，将原代心脏成纤维细胞接种于沉积有TTR的基质表面培养时，其纤维状肌动蛋白（F-actin）细胞骨架发生紊乱，黏着斑形成减少，细胞核形态变扁平；在该类基质上，成纤维细胞的集体迁移与单个细胞迁移速度均有所加快。此外，在修饰有TTR的微柱阵列表面培养的成纤维细胞，其细胞黏附能力较未修饰组降低，而增殖能力则有所提升。对覆盖有TTR的玻璃基质上培养的成纤维细胞进行转录组与蛋白质组分析后发现，培养48小时后炎症相关基因出现显著上调，这一结果提示了TTR相关疾病的进展特征。综合以上结果，本研究表明：沉积于组织细胞外基质中的TTR，可对心脏成纤维细胞的结构、功能以及基因表达产生影响。鉴于当前wtATTR的治疗方案不仅费用高昂、难以负担，且仅能延缓疾病进展，因此深入探究细胞适应不良机制，或可阐明全新的治疗靶点。