Journal
ACS BIOMATERIALS SCIENCE & ENGINEERING
Volume 5, Issue 3, Pages 1416-1425Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.8b01280
Keywords
alignment; osteogenic differentiation; valve disease; microenvironment; tissue engineering
Categories
Funding
- American Heart Association Postdoctoral Fellowship [13POST17220071]
- American Heart Association Scientist Development Grant [17SDG33680170]
- Hartwell Foundation
- National Science Foundation [CBET-0955172]
- Felton Family Endowment for Human Heart Valve Research at Seattle Children's Hospital
- National Institutes of Health [HL128745, NIH 1S10RR025502-01]
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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 \TIC 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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