Cardiac valves open and close 100,000 times a day, controlling unidirectional flow of the blood. The homeostasis of valve is largely maintained by the main cell population in the valve, termed valvular interstitial cells (VICs). VICs are fibroblasts with the capacity to produce the extracellular matrix components of the valve and the matrix remodeling enzymes. VICs have also been shown to participate in valvular diseases by differentiating into myofibroblasts or osteoblast-like cells. Traditionally, these cells have been cultured on polystyrene plates for studying their functions. However, we found that the very stiff plastic plates activate VICs into myofibroblasts. With the development of poly(ethylene glycol) based hydrogels, I was able to shown that hydrogels with physiologically relevant stiffness can serve as a better culture platform to not only preserve the native phenotype of the freshly isolated VICs, but also redirect activated VICs into a dormant fibroblast state (Fig 1). This finding help us understand how the physical cues from the matrix regulate the pathogenic phenotype of VICs and provide information that can be exploited for tissue engineering in future.
Freshly isolated VICs (P0 VICs) are activated on stiff gels and de-activated with reduction in substrate modulus.Freshly isolated VICs that have not been sub-cultured on plastic plates were seeded on stiff gels. Cell activation was examined on day 5 by α-SMA immunocytochemistry. Green: α-SMA. Blue: nuclei. A similar percentage of myofibroblasts was observed for P0 VICs on stiff gels compared with P3 VICs which have been expanded on plastic plate. After gel softening with light (stiff-to-soft gel), activated P0 VICs were de-activated with significant reduction in the number of myofibroblasts. Scale bar: 100μm.
Wang H., Haeger SM., Kloxin AK, Leinwand LA, Anseth KS. Redirecting valvular myofibroblasts into dormant fibroblasts through light-mediated reduction in substrate modulus.PLoS One7(7):e39969 (2012).