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Human induced pluripotent stem cell-derived vocal fold mucosa mimics development and responses to smoke exposure.

ABSTRACT: Development of treatments for vocal dysphonia has been inhibited by lack of human vocal fold (VF) mucosa models because of difficulty in procuring VF epithelial cells, epithelial cells' limited proliferative capacity and absence of cell lines. Here we report development of engineered VF mucosae from hiPSC, transfected via TALEN constructs for green fluorescent protein, that mimic development of VF epithelial cells in utero. Modulation of FGF signaling achieves stratified squamous epithelium from definitive and anterior foregut derived cultures. Robust culturing of these cells on collagen-fibroblast constructs produces three-dimensional models comparable to in vivo VF mucosa. Furthermore, we demonstrate mucosal inflammation upon exposure of these constructs to 5% cigarette smoke extract. Upregulation of pro-inflammatory genes in epithelium and fibroblasts leads to aberrant VF mucosa remodeling. Collectively, our results demonstrate that hiPSC-derived VF mucosa is a versatile tool for future investigation of genetic and molecular mechanisms underlying epithelium-fibroblasts interactions in health and disease.

SUBMITTER: Lungova V

PROVIDER: S-EPMC6760204 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Human induced pluripotent stem cell-derived vocal fold mucosa mimics development and responses to smoke exposure.

Lungova Vlasta V Chen Xia X Wang Ziyue Z Kendziorski Christina C Thibeault Susan L SL

Nature communications 20190924 1

Development of treatments for vocal dysphonia has been inhibited by lack of human vocal fold (VF) mucosa models because of difficulty in procuring VF epithelial cells, epithelial cells' limited proliferative capacity and absence of cell lines. Here we report development of engineered VF mucosae from hiPSC, transfected via TALEN constructs for green fluorescent protein, that mimic development of VF epithelial cells in utero. Modulation of FGF signaling achieves stratified squamous epithelium from ...[more]

PMID: 31551422

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Project description:Injuries of the vocal folds frequently heal with scar formation, which can have lifelong detrimental impact on voice quality. Current treatments to prevent or resolve scars of the vocal fold mucosa are highly unsatisfactory. In contrast, the adjacent oral mucosa is mostly resistant to scarring. These differences in healing tendency might relate to distinct properties of the fibroblasts populating oral and vocal fold mucosae. We thus established the in vitro cultivation of paired, near-primary vocal fold fibroblasts (VFF) and oral mucosa fibroblasts (OMF) to perform a basic cellular characterization and comparative cellular proteomics. VFF were significantly larger than OMF, proliferated more slowly, and exhibited a sustained TGF-β1-induced elevation of pro-fibrotic interleukin 6. Cluster analysis of the proteomic data revealed distinct protein repertoires specific for VFF and OMF. Further, VFF displayed a broader protein spectrum, particularly a more sophisticated array of factors constituting and modifying the extracellular matrix. Conversely, subsets of OMF-enriched proteins were linked to cellular proliferation, nuclear events, and protection against oxidative stress. Altogether, this study supports the notion that fibroblasts sensitively adapt to the functional peculiarities of their respective anatomical location and presents several molecular targets for further investigation in the context of vocal fold wound healing.Biological significanceMammalian vocal folds are a unique but delicate tissue. A considerable fraction of people is affected by voice problems, yet many of the underlying vocal fold pathologies are sparsely understood at the molecular level. One such pathology is vocal fold scarring - the tendency of vocal fold injuries to heal with scar formation -, which represents a clinical problem with highly suboptimal treatment modalities. This study employed proteomics to obtain comprehensive insight into the protein repertoire of vocal fold fibroblasts, which are the cells that predominantly synthesize the extracellular matrix in both physiological and pathophysiological conditions. Protein profiles were compared to paired fibroblasts from the oral mucosa, a neighboring tissue that is remarkably resistant to scarring. Bioinformatic analyses of the data revealed a number of pathways as well as single proteins (e.g. ECM-remodeling factors, transcription factors, enzymes) that were significantly different between the two fibroblast types. Thereby, this study has revealed novel interesting molecular targets which can be analyzed in the future for their impact on vocal fold wound healing.

Dataset Information

Human induced pluripotent stem cell-derived vocal fold mucosa mimics development and responses to smoke exposure.

Publications

Human induced pluripotent stem cell-derived vocal fold mucosa mimics development and responses to smoke exposure.

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