Mesenchymal stem cell therapy for laryngotracheal stenosis: A systematic review of preclinical studies

<div><p>Background</p><p>Laryngotracheal stenosis (LTS) can be either congenital or acquired. Laryngeal stenosis is most often encountered after prolonged intubation. The mechanism for stenosis following intubation is believed to be hypertrophic scarring. Mesenchymal stem cells (MSCs) therapy has shown promising results in regenerative medicine. We aimed to systematically review the literature on MSC therapy for stenosis of the conductive airways.</p><p>Methods</p><p>PubMed, EMBASE, Google Scholar and the Cochrane Library were systematically searched from January 1980–January 2017 with the purpose of identifying all studies addressing the effect of MSC therapy on the airway. We assessed effect on inflammation, fibrosis, and MSC as a component in tissue engineering for treating defects in the airway.</p><p>Results</p><p>We identified eleven studies (n = 256 animals) from eight countries evaluating the effect of MSCs as a regenerative therapy in the upper airways. The studies indicate that MSC therapy may lead to a more constructive inflammatory response as well as support tissue regeneration.</p><p>Conclusion</p><p>There may be a favorable effect of MSCs in inhibiting inflammation and as a component in tissue engineering. Given the heterogeneous nature of the included animal studies, any clear conclusion regarding the effect of tracheal stenosis in human subjects cannot be drawn. The included preclinical studies are however encouraging for further research.</p></div

Overview of studies: MSCs and inflammation in the airways.

<p>Overview of studies: MSCs and inflammation in the airways.</p

Study results of the effect of MSCs on tissue engineering.

<p>Study results of the effect of MSCs on tissue engineering.</p

High miR-21 expression is associated with poor survival.

<p>Top: Waterfall plot of miR-21 expression in 86 OSCCs. miR-21 expression was assessed by in situ hybridization and converted to the area occupied by miR-21 (blue ) times the mean intensity of the blue signal. The cut-off between the upper, middle and lower tertile are depicted by blue, yellow and green bars, respectively. Bottom: Cox regression survival curve for disease free survival, based on miR-21 expression tertiles. Low miR-21 expression is associated with a better survival (p = 0.032).</p

Hazard ratios from univariate analysis for disease free survival in OSCC.

<p>On the right hazard ratios including 95% confidence intervals are displayed. See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0095193#pone-0095193-t001" target="_blank">Table 1</a> for details.</p

Mesenchymal Stem Cell Therapy for the Treatment of Vocal Fold Scarring: A Systematic Review of Preclinical Studies

<div><p>Objectives</p><p>Therapy with mesenchymal stem cells exhibits potential for the development of novel interventions for many diseases and injuries. The use of mesenchymal stem cells in regenerative therapy for vocal fold scarring exhibited promising results to reduce stiffness and enhance the biomechanical properties of injured vocal folds. This study evaluated the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring.</p><p>Data Sources</p><p>PubMed, Embase, the Cochrane Library and Google Scholar were searched.</p><p>Methods</p><p>Controlled studies that assessed the biomechanical effects of mesenchymal stem cell therapy for the treatment of vocal fold scarring were included. Primary outcomes were viscoelastic properties and mucosal wave amplitude.</p><p>Results</p><p>Seven preclinical animal studies (n = 152 single vocal folds) were eligible for inclusion. Evaluation of viscoelastic parameters revealed a decreased dynamic viscosity (η’) and elastic modulus (G’), i.e., decreased resistance and stiffness, in scarred vocal folds treated with mesenchymal stem cells compared to non-treated scarred vocal folds. Mucosal wave amplitude was increased in scarred vocal folds treated with mesenchymal stem cells vs. non-treated scarred vocal folds.</p><p>Conclusion</p><p>The results from these studies suggest an increased regenerative effect of therapy with mesenchymal stem cells for scarred vocal folds and are encouraging for further clinical studies.</p></div

Multivariate model of factors associated with disease free survival.

<p>Legend: The remaining factors in multivariate Cox regression after backwards elimination. Only miR-21 TBS and perineural invasion remained as independent factors influencing survival.</p

Univariate analysis of factors associated with disease free survival in OSCC.

<p>Footnote: * significant factors associated with survival.</p

Digital image analysis of in situ hybridization.

<p>The miR-21 expression in the stroma was estimated using digital image analysis. Image (A), (B), (C) and (D) overview the image-analysis process, where (A) is the original cytokeratin stained image, which is used to delineate epithelial tumor cells, seen as green color in (B). Original image of miR-21 ISH on serial section from same tumor, where the ISH signal is quantitated specifically in the stroma area (blue signal). The red color in (B) represents stroma area negative for miR-21. See methods for a detailed description of the image analysis process.</p

The miR-21 in situ hybridization is specific.

<p>Comparison between the miR-21 probe (A) and the scrambled probe (B) in the same tumor. The scrambled probe (B) gave no expression. Comparison between miR-21 probe (C) and U6 probe (D) in the same tumor. The U6 probe gives a positive nuclear expression in virtually every cell.</p