Journal article
Calcium Signaling Regulates Valvular Interstitial Cell Alignment and Myofibroblast Activation in Fast-relaxing Boronate Hydrogels
Macromolecular bioscience, Vol.20(12), pp.e2000268-e2000268
09/13/2020
DOI: 10.1002/mabi.202000268
PMCID: PMC7773027
PMID: 32924320
Abstract
The role viscoelasticity plays in fibrotic disease progression is an emerging area of interest. Here, a fast-relaxing hydrogel system is exploited to investigate potential crosstalk between calcium signaling and mechanotransduction. Poly(ethylene glycol) (PEG) hydrogels containing boronate and triazole crosslinkers are synthesized, with varying ratios of boronate to triazole crosslinks to systematically vary the extent of stress relaxation in the final hydrogel formulation. Valvular interstitial cells (VICs) are encapsulated in these fast-relaxing scaffolds, and the role that viscoelasticity plays on VIC alignment and myofibroblast activation is investigated. VICs cultured in hydrogels with the highest levels of stress relaxation (90%) exhibit a spread morphology by day 1 and are highly aligned (80 ± 2 %) by day 5. Key myofibroblast markers, including α-smooth muscle actin (αSMA) and collagen 1a1 (COLL1A1), are also significantly elevated. VIC myofibroblast activation decreases by 42 ± 18% through inhibition of mechanotransduction, independently of VIC morphology and alignment. Calcium signaling through a transient receptor potential vanilloid 4 (TRPV4) is found to regulate VIC spreading, alignment, and myofibroblast activation in a time dependent manner. Inhibition of calcium signaling at early time points results in disturbed cell alignment, decreased mechanotransduction, and diminished myofibroblast activation, while inhibition at later time points only causes partially reduced myofibroblast activation. These results suggest a potential crosstalk mechanism between calcium signaling and mechanotransduction, where calcium signaling acts upstream of mechanosensing and can interestingly also regulate VIC myofibroblast activation independently of mechanotransduction.
Valvular interstitial cell (VIC) alignment and myofibroblast activation was investigated in a 3D fast-relaxing hydrogel scaffold with tunable viscoelasticity. VIC spreading and alignment correlated with higher extents of matrix viscoelasticity and stress relaxation via activating calcium channels. A potential crosstalk between viscoelasticity, calcium signaling, and mechanotransduction was proposed, which provides new insights into potential targets for valvular tissue fibrosis treatment.
Details
- Title: Subtitle
- Calcium Signaling Regulates Valvular Interstitial Cell Alignment and Myofibroblast Activation in Fast-relaxing Boronate Hydrogels
- Creators
- Hao Ma - University of Colorado BoulderLaura J. Macdougall - University of Colorado BoulderAndrea Gonzalez Rodriguez - University of Colorado BoulderMegan E. Schroeder - University of Colorado BoulderDilara Batan - University of Colorado BoulderRobert M. Weiss - University of IowaKristi S. Anseth - University of Colorado Boulder
- Resource Type
- Journal article
- Publication Details
- Macromolecular bioscience, Vol.20(12), pp.e2000268-e2000268
- DOI
- 10.1002/mabi.202000268
- PMID
- 32924320
- PMCID
- PMC7773027
- NLM abbreviation
- Macromol Biosci
- ISSN
- 1616-5187
- eISSN
- 1616-5195
- Grant note
- DOI: 10.13039/100000968, name: American Heart Association, award: 20PRE35200068; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 HL132353
- Language
- English
- Date published
- 09/13/2020
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984359775702771
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