Valvular interstitical cells (VIC)
Valvular interstitial cells (VIC) represent a crucial and heterogeneous cell population through the leaflet, distributed in all layers (23). They are the most abundant cell type in the heart valves and resemble, among others, fibroblasts and smooth muscle cells. VIC represent a dynamic population responsible for the synthesis of extracellular matrix and matrix degrading enzymes. Thus, they regulate and remodel collagen and other essential components to assure the continuous valve repair (23). The activation of VICs (including the production and secretion of matrix) is regulated by mechanical stretch, local cellular signaling (e.g. interaction with other types of cells from heart valves such as valvular endothelial cells), microstructural factors, and hemodynamic environments (24). It has also been theorized that VIC contraction, in response to environment stimuli, may facilitate cell-to-cell communication and act as a role in maintaining leaflet homeostasis (25). The ability to answer to the surrounding environment makes VIC highly plastic, with at least 5 distinct phenotypes described, from a quiescent to an activated form (the 5 distinct VIC phenotypes include embryonic progenitor endothelial/ mechenchymal cells, quiescent VIC, activated VIC, postdevelopmental/ adult progenitor VIC and osteoblastic VIC) (23).
Although it may be interesting to explore all phenotypes, the quiescent and the activated forms are the most relevant in this context. VIC in adult valves are quiescent, without activity, with fibroblasts characteristics (26). The plasticity of VICs is important for development but plays also an important role in pathologic processes (19). VIC plasticity is regulated by multiple factors, such as environmental factors and host factor as age.
In the disease states, VIC progress from the quiescent fibroblast-like phenotype to a contractile form, with enhanced production and secretion of extracellular matrix, cytokines, proteases and growth factors (9, 10). VIC progression has direct consequences on the heart valve function, as it has been shown that VIC contraction have measurable effects on leaflet stiffness (28). When the activation persists and is prolonged, VIC can differentiate into osteoblast-like cells (the osteoblatic VIC phenotype), leading to calcific nodule formation and valve calcifications (29). However, activation of VIC is not a definitive process, as it can be reversiblly modulated (29).