Retinoic Acid Depletion Induces Keratinizing Squamous Differentiation in Human Middle Ear Epithelial Cell Cultures

Choi, Jae Young; Cho, Kyou-Nam; Yoo, Ki-Han; Shin, Jung Soon; Yoon, Joo Heon

doi:10.1080/0036554021000028097

Cited by 13 publications

(14 citation statements)

References 12 publications

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“…However, there are no published studies on the relationship between VAD and SMG, although there are reports that VAD decreases mucin production from cultured airway epithelial cells and causes squamous metaplasia (15)(16)(17). Therefore, we conducted this study to investigate the effects of VAD on SMG in a mouse model of VAD.…”

Section: Introductionmentioning

confidence: 91%

Vitamin A Deficiency Induces Fluid Hyposecretion from the Airway Submucosal Glands of Mice

Kim

Lee

Joo

et al. 2012

The Journal of Nutrition

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Vitamin A deficiency (VAD) alters the phenotype of airway epithelium and attenuates the epithelial defense system, and many studies have reported the association of VAD with respiratory disease. In this study, we investigated changes in submucosal glands (SMG) in a mouse model of VAD. C57BL/6 mice were fed a vitamin A-devoid diet and the others were fed a control diet (1.2 mg retinol/kg). The areas of serous and mucous cells of SMG were measured in 4-, 8-, and 20-wk-old male mice. The volume and lysozyme concentration of glandular secretions were also measured. The 2 groups did not differ in body weight or general morbidity at 3-10 wk of age, although serum retinol concentrations were greater in the control mice than in the VAD mice after 4 wk. Upon histological evaluation, we found that the areal ratio of serous cells:total SMG cells was significantly lower after 8 wk in the VAD mice compared with the control mice, although the total area of SMG did not differ between groups throughout the 20-wk experiment. The number of secretory bubbles did not differ between the groups, but total secretion volume was reduced by 35% in 8-wk-old VAD mice compared with controls. Furthermore, the concentration of lysozyme in secretions from 8-wk-old VAD mice was also less than in controls, compounding the effect of diminished secretion volume. In this study, we found serous cell hypotrophy/hypoplasia and dysfunction in VAD mice, which may contribute to the susceptibility to airway infection linked to VAD.

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Section: Introductionmentioning

confidence: 91%

Vitamin A Deficiency Induces Fluid Hyposecretion from the Airway Submucosal Glands of Mice

Kim

Lee

Joo

et al. 2012

The Journal of Nutrition

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“…Recently, however, Uematsu et al (22) reported that a low concentration of RA (which is produced by TLR5 + DCs in the SI-LP) seems to be necessary for Th17 cell differentiation. Moreover, others have shown that RA depletion in a human primary epithelial cell culture system induces keratinizing squamous differentiation and reduces expression of mucin genes (23).…”

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confidence: 99%

Downregulation of Th17 Cells in the Small Intestine by Disruption of Gut Flora in the Absence of Retinoic Acid

Cha

Chang

et al. 2010

The Journal of Immunology

149

108

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Retinoic acid (RA), a well-known vitamin A metabolite, mediates inhibition of the IL-6-driven induction of proinflammatory Th17 cells and promotes anti-inflammatory regulatory T cell generation in the presence of TGF-β, which is mainly regulated by dendritic cells. To directly address the role of RA in Th17/regulatory T cell generation in vivo, we generated vitamin A-deficient (VAD) mice by continuous feeding of a VAD diet beginning in gestation. We found that a VAD diet resulted in significant inhibition of Th17 cell differentiation in the small intestine lamina propria by as early as age 5 wk. Furthermore, this diet resulted in low mRNA expression levels of IL-17, IFN regulatory factor 4, IL-21, IL-22, and IL-23 without alteration of other genes, such as RORγt, TGF-β, IL-6, IL-25, and IL-27 in the small intestine ileum. In vitro results of enhanced Th17 induction by VAD dendritic cells did not mirror in vivo results, suggesting the existence of other regulation factors. Interestingly, the VAD diet elicited high levels of mucin MUC2 by goblet cell hyperplasia and subsequently reduced gut microbiome, including segmented filamentous bacteria. Much like wild-type mice, the VAD diet-fed MyD88−/−TRIF−/− mice had significantly fewer IL-17–secreting CD4+ T cells than the control diet-fed MyD88−/−TRIF−/− mice. The results strongly suggest that RA deficiency altered gut microbiome, which in turn inhibited Th17 differentiation in the small intestine lamina propria.

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“…A substantial greater risk of developing otitis media has been seen in the subset that harbors a subclinical defi ciency as compared to normal individuals. Several studies on animals and cell cultures have shown the metaplasia of middle ear epithelium to keratinizing squamous epithelium when subjected to vitamin A-defi cient environment thus inducing cholesteatoma [4,5]. This possibly could be the adaptation of the specialized epithelium to unfavorable environment for survival.…”

Section: Discussionmentioning

confidence: 99%

“…This possibly could be the adaptation of the specialized epithelium to unfavorable environment for survival. Studies performed on the transcriptional regulation of epithelial differentiation using gene markers by Choi et al [5] showed that in a vitamin A-defi cient environment, cornifi n-α, which is the gene marker for squamous differentiation was up regulated, and MUC5AC, MUC8 which are the mucin markers were down regulated with a resultant induction of cholesteatoma. When these cell cultures were further subjected to treatment with Vitamin A there was complete reversal of gene regulation changes [6].…”

Section: Discussionmentioning

confidence: 99%

Role of vitamin A in the evolution of cholesteatoma

Rao¹,

Srinivas

Humbarwadi

et al. 2009

Indian J Otolaryngol Head Neck Surg

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The role of vitamin A in the maintenance of epithelial integrity is well known. Several animal studies have dealt with the induction of cholesteatoma in vitamin A defi ciency states and prevention and treatment of otitis media with vitamin A treatment. We treated fi ve patients of cholesteatoma with vitamin A oral supplements and no other treatment and found signifi cant resolution of cholesteatoma in four patients. Though this may not be an explanation in every case of cholesteatoma, our study highlights that there is a subset of patients with vitamin A defi cient cholesteatoma who could substantially benefi t from intervention with this wonderful vital amine.

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Retinoic Acid Depletion Induces Keratinizing Squamous Differentiation in Human Middle Ear Epithelial Cell Cultures

Abstract: This study shows that RA depletion induces keratinizing squamous differentiation in NHMEE cell cultures. This finding supports the hypothesis that middle ear cholesteatoma originates from metaplastic middle ear mucosa.

Cited by 13 publications

References 12 publications

Vitamin A Deficiency Induces Fluid Hyposecretion from the Airway Submucosal Glands of Mice

Vitamin A Deficiency Induces Fluid Hyposecretion from the Airway Submucosal Glands of Mice

Downregulation of Th17 Cells in the Small Intestine by Disruption of Gut Flora in the Absence of Retinoic Acid

Role of vitamin A in the evolution of cholesteatoma

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