Key result
Stripe micropatterning promoted spreading, activation, and osteogenic differentiation of human aortic valve interstitial cells, with diseased cells exhibiting greater susceptibility.
Why the study?
It is unclear how valve interstitial cell alignment in their 3D microenvironment drives phenotype or influences cellular responses to biochemical cues in physiological or pathological conditions.
3D micropatterning reveals that valve interstitial cell alignment and biochemical cues like bFGF differentially regulate osteogenic differentiation in healthy versus diseased human aortic valve cells.
Caution advised for micropatterned valve biomaterials; leaves open whether topography modulation affects calcification progression in patients.
Calcific aortic valve disease (CAVD) is the third leading cause of cardiovascular disease. CAVD exhibits progressive disruption of the normally highly organized and aligned extracellular matrix (ECM) structure within the valve leaflets simultaneously with myofibroblastic and/or osteogenic differentiation of indigenous endogenous valve interstitial cells (VIC). It is unclear how the alignment of VIC within their 3D microenvironment drives VIC phenotype or how alignment affects cellular responses to biochemical cues in physiological or pathological conditions. In this study, we implement a photolithographic technique to control the alignment and elongation of both normal and diseased human aortic VIC (HAVIC) within microengineered 3D hydrogels consisting of methacrylated hyaluronic acid and methacrylated gelatin. Stripe micropatterning created distinct alignment of HAVIC within a 3D culture system, which promoted spreading and enhanced their activation and osteogenic differentiation in pro-osteogenic conditions. HAVIC from a patient with CAVD exhibited greater susceptibility to myofibroblastic and osteogenic differentiation in culture. The roles of conjugated basic fibroblastic growth factor (bFGF) and RhoA/ROCK pathway in regulating HAVIC phenotypes were also investigated in the presence of aligned microtopography. The addition of bFGF was preventative to osteogenic differentiation for healthy HAVIC; however, it promoted osteogenic differentiation in diseased HAVIC. Inhibition of the ROCK pathway only decreased osteogenic differentiation for diseased HAVIC in the aligned formation. Collectively, these results improve our knowledge of the effects that VIC alignment has on VIC phenotypes and valve disease progression. The cell culture platform also enables a better understanding of the interplay between topography, biochemical cues, and VIC differentiation and provides information useful for directing differentiation as well as valve tissue regeneration.
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Xu et al. (2019) studied Calcific aortic valve disease. Stripe micropatterning and biochemical cues (bFGF, ROCK pathway inhibition) was evaluated on Cell spreading, activation, and osteogenic differentiation. Stripe micropatterning promoted spreading, activation, and osteogenic differentiation of human aortic valve interstitial cells, with diseased cells exhibiting greater susceptibility.
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