Matrix Adhesiveness Regulates Myofibroblast Differentiation from Vocal Fold Fibroblasts in a Bio-orthogonally Cross-linked Hydrogel

Simple item page
Author(s)Song, Jiyeon
Author(s)Gao, Hanyuan
Author(s)Zhang, He
Author(s)George, Olivia J.
Author(s)Hillman, Ashlyn S.
Author(s)Fox, Joseph M.
Author(s)Jia, Xinqiao
Date Accessioned2023-01-06T20:53:52Z
Date Available2023-01-06T20:53:52Z
Publication Date2022-11-23
DescriptionThis document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Applied Materials and Interfaces, copyright © 2022 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acsami.2c13852. This article will be embargoed until 11/23/2023.
AbstractRepeated mechanical and chemical insults cause an irreversible alteration of extracellular matrix (ECM) composition and properties, giving rise to vocal fold scarring that is refractory to treatment. Although it is well known that fibroblast activation to myofibroblast is the key to the development of the pathology, the lack of a physiologically relevant in vitro model of vocal folds impedes mechanistic investigations on how ECM cues promote myofibroblast differentiation. Herein, we describe a bio-orthogonally cross-linked hydrogel platform that recapitulates the alteration of matrix adhesiveness due to enhanced fibronectin deposition when vocal fold wound healing is initiated. The synthetic ECM (sECM) was established via the cycloaddition reaction of tetrazine (Tz) with slow (norbornene, Nb)- and fast (trans-cyclooctene, TCO)-reacting dienophiles. The relatively slow Tz–Nb ligation allowed the establishment of the covalent hydrogel network for 3D cell encapsulation, while the rapid and efficient Tz–TCO reaction enabled precise conjugation of the cell-adhesive RGDSP peptide in the hydrogel network. To mimic the dynamic changes of ECM composition during wound healing, RGDSP was conjugated to cell-laden hydrogel constructs via a diffusion-controlled bioorthognal ligation method 3 days post encapsulation. At a low RGDSP concentration (0.2 mM), fibroblasts residing in the hydrogel remained quiescent when maintained in transforming growth factor beta 1 (TGF-β1)-conditioned media. However, at a high concentration (2 mM), RGDSP potentiated TGF-β1-induced myofibroblast differentiation, as evidenced by the formation of an actin cytoskeleton network, including F-actin and alpha-smooth muscle actin. The RGDSP-driven fibroblast activation to myofibroblast was accompanied with an increase in the expression of wound healing-related genes, the secretion of profibrotic cytokines, and matrix contraction required for tissue remodeling. This work represents the first step toward the establishment of a 3D hydrogel-based cellular model for studying myofibroblast differentiation in a defined niche associated with vocal fold scarring.
SponsorThis work was supported in part by the National Institutes of Health (NIDCD R01DC014461 and NIDCR R01DE029655), National Science Foundation (NSF, DMR 1809612), and the Delaware Bioscience Center for Advanced Technology (DECAT 12A00448). Instrumentation and core facility support was made possible by NIH (S10 OD016361, P20 GM103446, and P20GM139760) and NSF (CHE-0840401, CHE- 1229234, and IIA-1301765) grants. The authors also acknowledge the use of facilities and instrumentation supported by NSF through the University of Delaware Materials Research Science and Engineering Center (DMR-2011824).
CitationSong, Jiyeon, Hanyuan Gao, He Zhang, Olivia J. George, Ashlyn S. Hillman, Joseph M. Fox, and Xinqiao Jia. “Matrix Adhesiveness Regulates Myofibroblast Differentiation from Vocal Fold Fibroblasts in a Bio-Orthogonally Cross-Linked Hydrogel.” ACS Applied Materials & Interfaces 14, no. 46 (November 23, 2022): 51669–82. https://doi.org/10.1021/acsami.2c13852.
ISSN1944-8252
URLhttps://udspace.udel.edu/handle/19716/32034
Languageen_US
PublisherACS Applied Materials and Interfaces
Keywordsvocal fold fibroblasts
Keywordsmyofibroblasts
Keywordscell adhesive peptide
Keywordstransforming growth factor beta1
Keywordstetrazine ligation
TitleMatrix Adhesiveness Regulates Myofibroblast Differentiation from Vocal Fold Fibroblasts in a Bio-orthogonally Cross-linked Hydrogel
TypeArticle
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Matrix Adhesiveness Regulates Myofibroblast Differentiation from Vocal Fold Fibroblasts in a Bio-orthogonally Cross-linked Hydrogel.pdf
Size:
9.72 MB
Format:
Adobe Portable Document Format
Description:
Main article
Download
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
2.22 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Open Access Publications
Open Access Publications