Spatial Regulation of Valve Interstitial Cell Phenotypes within Three-Dimensional Micropatterned Hydrogels.
Bin DuanCharlie XuShoshana DasJonathan M ChenJonathan T ButcherPublished in: ACS biomaterials science & engineering (2019)
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.
Keyphrases
- aortic valve
- mesenchymal stem cells
- extracellular matrix
- hyaluronic acid
- aortic stenosis
- transcatheter aortic valve replacement
- bone marrow
- aortic valve replacement
- transcatheter aortic valve implantation
- mitral valve
- growth factor
- cardiovascular disease
- stem cells
- healthcare
- drug delivery
- left ventricular
- high throughput
- anti inflammatory
- single cell
- coronary artery disease
- cell proliferation
- cell therapy
- oxidative stress
- high resolution
- induced apoptosis
- metabolic syndrome
- pulmonary hypertension
- cardiovascular risk factors
- photodynamic therapy
- pulmonary arterial hypertension
- social media
- cell cycle arrest
- tissue engineering
- coronary artery