Use of Patterned Collagen Coated Slides to Study Normal and Scleroderma Lung Fibroblast Migration.
Use of Patterned Collagen Coated Slides to Study Normal and Scleroderma Lung Fibroblast Migration.
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DOI：
10.1038/s41598-017-02621-3
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发表时间：
2017-06-01
影响因子：
4.6
通讯作者：
Stratton R
中科院分区：
文献类型：
--
作者：
Ahmed Abdi B;Lopez H;Karrar S;Renzoni E;Wells A;Tam A;Etomi O;Hsuan JJ;Martin GR;Shiwen X;Denton CP;Abraham D;Stratton R
系统性硬化症（SSc）是一种影响皮肤和内脏器官的扩散性纤维化疾病。我们的目的是建立SSc中致病性成纤维细胞迁移的模型，以确定增强因子，测量迁移细胞对基础细胞外基质（ECM）的影响，并测试可能的治疗抑制剂。使用新型图案化胶原基质来研究来自SSc患者和健康对照的皮肤和肺成纤维细胞的对齐和迁移。正常肺而不是皮肤成纤维细胞一致地伸长并与底层胶原对齐，并依赖于PDGF或血清迁移。SSc肺成纤维细胞保持生长因子依赖性，没有更快地迁移，并且较少限制胶原蛋白的排列。多种胶原蛋白脯氨酸和赖氨酸修饰酶被确定在SSc，但不控制成纤维细胞外基质制剂，表明不同水平的ECM修改的病变细胞。迁移细胞的分析揭示了一种可能的SCF/c-Kit旁分泌机制，有助于通过细胞亚群迁移。肝素结合包括PDGF和SCF在内的配体，伊马替尼阻断下游酪氨酸激酶受体，两者单独抑制肺成纤维细胞迁移，但在SSc细胞中显示协同作用。SSc患者的病理性肺成纤维细胞在迁移过程中修饰ECM，但仍保持生长因子依赖性和对抑制剂敏感。
Systemic sclerosis (SSc) is a spreading fibrotic disease affecting the skin and internal organs. We aimed to model pathogenic fibroblast migration in SSc in order to identify enhancing factors, measure the effect of migrating cells on underlying extracellular matrix (ECM) and test possible therapeutic inhibitors. Novel patterned collagen substrates were used to investigate alignment and migration of skin and lung fibroblasts from SSc patients and healthy controls. Normal lung but not skin fibroblasts consistently elongated and aligned with underlying collagen and migrated dependent on PDGF or serum. SSc lung fibroblasts remained growth factor dependent, did not migrate more rapidly and were less restricted to alignment of the collagen. Multiple collagen proline and lysine-modifying enzymes were identified in SSc but not control fibroblast extracellular matrix preparations, indicating differential levels of ECM modification by the diseased cells. Profiling of migrating cells revealed a possible SCF/c-Kit paracrine mechanism contributing to migration via a subpopulation of cells. Heparin, which binds ligands including PDGF and SCF, and imatininib which blocks downstream tyrosine kinase receptors, both inhibited lung fibroblast migration individually but showed synergy in SSc cells. Pathologic lung fibroblasts from SSc patients modify ECM during migration but remain growth factor dependent and sensitive to inhibitors.