Ren Xiaoou, Getschman Anthony E, Hwang Samuel, Volkman Brian F, Klonisch Thomas, Levin David, Zhao Min, Santos Susy, Liu Song, Cheng Jasmine, Lin Francis
Department of Physics and Astronomy, University of Manitoba, 30A Sifton Rd, 301 Allen Bldg, Winnipeg, MB R3T 2N2, Canada.
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Lab Chip. 2021 Apr 20;21(8):1527-1539. doi: 10.1039/d0lc01194k.
A microfluidics-based three-dimensional skin-on-chip (SoC) model is developed in this study to enable quantitative studies of transendothelial and transepithelial migration of human T lymphocytes in mimicked skin inflammatory microenvironments and to test new drug candidates. The keys results include 1) CCL20-dependent T cell transmigration is significantly inhibited by an engineered CCL20 locked dimer (CCL20LD), supporting the potential immunotherapeutic use of CCL20LD for treating skin diseases such as psoriasis; 2) transepithelial migration of T cells in response to a CXCL12 gradient mimicking T cell egress from the skin is significantly reduced by a sphingosine-1-phosphate (S1P) background, suggesting the role of S1P for T cell retention in inflamed skin tissues; and 3) T cell transmigration is induced by inflammatory cytokine stimulated epithelial cells in the SoC model. Collectively, the developed SoC model recreates a dynamic multi-cellular micro-environment that enables quantitative studies of T cell transmigration at a single cell level in response to physiological cutaneous inflammatory mediators and potential drugs.
在本研究中，开发了一种基于微流控技术的三维皮肤芯片（SoC）模型，用于在模拟的皮肤炎症微环境中对人T淋巴细胞的跨内皮和跨上皮迁移进行定量研究，并测试新的候选药物。关键结果包括：1）工程化的CCL20锁定二聚体（CCL20LD）显著抑制了CCL20依赖性T细胞迁移，支持CCL20LD在治疗银屑病等皮肤病方面的潜在免疫治疗用途；2）模拟T细胞从皮肤逸出的CXCL12梯度刺激下，鞘氨醇-1-磷酸（S1P）背景显著降低了T细胞的跨上皮迁移，表明S1P在炎症皮肤组织中对T细胞滞留的作用；3）在SoC模型中，炎症细胞因子刺激上皮细胞可诱导T细胞迁移。总体而言，所开发的SoC模型重建了一个动态的多细胞微环境，能够在单细胞水平上对T细胞迁移进行定量研究，以响应生理性皮肤炎症介质和潜在药物。
