A novel human arterial wall-on-a-chip to study endothelial inflammation and vascular smooth muscle cell migration in early atherosclerosis.
Chengxun SuNishanth Venugopal MenonXiaohan XuYu Rong TeoHuan CaoRinkoo DalanChor Yong TayHan Wei HouPublished in: Lab on a chip (2021)
Mechanistic understanding of atherosclerosis is largely hampered by the lack of a suitable in vitro human arterial model that recapitulates the arterial wall structure, and the interplay between different cell types and the surrounding extracellular matrix (ECM). This work introduces a novel microfluidic endothelial cell (EC)-smooth muscle cell (SMC) 3D co-culture platform that replicates the structural and biological aspects of the human arterial wall for modeling early atherosclerosis. Using a modified surface tension-based ECM patterning method, we established a well-defined intima-media-like structure, and identified an ECM composition (collagen I and Matrigel mixture) that retains the SMCs in a quiescent and aligned state, characteristic of a healthy artery. Endothelial stimulation with cytokines (IL-1β and TNFα) and oxidized low-density lipoprotein (oxLDL) was performed on-chip to study various early atherogenic events including endothelial inflammation (ICAM-1 expression), EC/SMC oxLDL uptake, SMC migration, and monocyte-EC adhesion. As a proof-of-concept for drug screening applications, we demonstrated the atheroprotective effects of vitamin D (1,25(OH)2D3) and metformin in mitigating cytokine-induced monocyte-EC adhesion and SMC migration. Overall, the developed arterial wall model facilitates quantitative and multi-factorial studies of EC and SMC phenotype in an atherogenic environment, and can be readily used as a platform technology to reconstitute multi-layered ECM tissue biointerfaces.
Keyphrases
- endothelial cells
- extracellular matrix
- smooth muscle
- high glucose
- low density lipoprotein
- high throughput
- cell migration
- single cell
- cardiovascular disease
- oxidative stress
- poor prognosis
- vascular endothelial growth factor
- bone marrow
- rheumatoid arthritis
- high resolution
- metabolic syndrome
- cell therapy
- pluripotent stem cells
- peripheral blood
- electronic health record
- reduced graphene oxide
- cardiovascular risk factors
- adverse drug
- gold nanoparticles
- binding protein
- staphylococcus aureus