stratified epithelia
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Author(s):  
Kendall J Lough ◽  
Kevin M Byrd ◽  
Carlos P Descovich ◽  
Danielle C Spitzer ◽  
Abby J Bergman ◽  
...  

2019 ◽  
Vol 116 (35) ◽  
pp. 17361-17370 ◽  
Author(s):  
Eduardo Soares ◽  
Quan Xu ◽  
Qingqing Li ◽  
Jieqiong Qu ◽  
Yuxuan Zheng ◽  
...  

Mutations in transcription factor p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. The underlying cellular and molecular mechanism is however not yet understood. We established an epidermal commitment model using human induced pluripotent stem cells (iPSCs) and characterized differentiation defects of iPSCs derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations. Transcriptome analyses revealed stepwise cell fate transitions during epidermal commitment: Specification from multipotent simple epithelium to basal stratified epithelia and ultimately to the mature epidermal fate. Differentiation defects of EEC iPSCs caused by p63 mutations occurred during the specification switch from the simple epithelium to the basal-stratified epithelial fate. Single-cell transcriptome and pseudotime analyses of cell states identified mesodermal activation that was associated with the deviated commitment route of EEC iPSCs. Integrated analyses of differentially regulated genes and p63-dependent dynamic genomic enhancers during epidermal commitment suggest that p63 directly controls epidermal gene activation at the specification switch and has an indirect effect on mesodermal gene repression. Importantly, inhibitors of mesodermal induction enhanced epidermal commitment of EEC iPSCs. Our findings demonstrate that p63 is required for specification of stratified epithelia, and that epidermal commitment defects caused by p63 mutations can be reversed by repressing mesodermal induction. This study provides insights into disease mechanisms underlying stratified epithelial defects caused by p63 mutations and suggests potential therapeutic strategies for the disease.


2019 ◽  
Vol 28 (5) ◽  
pp. 536-542 ◽  
Author(s):  
Ryosuke Saigusa ◽  
Takashi Yamashita ◽  
Shunsuke Miura ◽  
Megumi Hirabayashi ◽  
Kouki Nakamura ◽  
...  

2018 ◽  
Author(s):  
Eduardo Soares ◽  
Quan Xu ◽  
Qingqing Li ◽  
Jieqiong Qu ◽  
Yuxuan Zheng ◽  
...  

AbstractMutations in transcription factor p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. The underlying cellular and molecular mechanism is however not yet understood. We established an epidermal commitment model using human induced pluripotent stem cells (iPSCs) and characterized differentiation defects of iPSCs derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations. Transcriptome analyses revealed distinct step-wise cell fate transitions during epidermal commitment; from multipotent simple epithelium to basal stratified epithelia, and ultimately to the mature epidermal fate. Differentiation defects of EEC iPSCs caused by mutant p63 occurred during the specification switch from the simple epithelium to the basal stratified epithelial fate. Single-cell transcriptome and pseudotime analyses identified signatures of embryonic epithelial-mesenchymal transition (EMT) associated with the deviated commitment route of EEC iPSCs. Repressing mesodermal activation reversed the EMT and enhanced epidermal commitment. Our findings demonstrate that p63 is required for specification of stratified epithelia, probably by repressing embryonic EMT during epidermal commitment. This study provides insights into disease mechanisms underlying stratified epithelial defects caused by p63 mutations and suggests potential therapeutic strategies for the disease.Significance statementMutations in p63 cause several developmental disorders with defects of epithelial related organs and tissues including the epidermis. Our study is to dissect the unknown cellular and molecular pathomechanism. We utilized human induced pluripotent stem cells (iPSCs) derived from ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome patients carrying p63 mutations and studied transcriptome changes during differentiation of these cells to epidermal cells. Our analyses showed that the specification of the proper epithelial cell fate was affected by p63 EEC mutations, with an abnormal embryonic epithelial-mesenchymal transition (EMT). Repressing mesodermal activation reversed the EMT and enhanced epidermal commitment. This study provides insights into disease mechanisms associated with p63 mutations and suggests potential therapeutic strategies.


2018 ◽  
Vol 399 (9) ◽  
pp. 1107-1111 ◽  
Author(s):  
Georgios Pampalakis ◽  
Eleni Zingkou ◽  
Georgia Sotiropoulou

Abstract Vaginal cancer is rare and largely unexplored. We found here that kallikrein-related peptidase 5 (KLK5) is coordinately expressed along with other KLKs in all stratified epithelia, including vagina, pointing to potential role(s) in differentiation. Further, we propose that KLK5 could be implicated in vaginal cancer development based on the fact that Klk5−/− mice are prone to develop vaginal tumors when exposed to 7,12-dimethylbenz[a]anthracene. Nf-κb activation is markedly enhanced in Klk5−/−, leading to increased resistance to apoptosis of mutated vaginal cells. This explains the higher tumor numbers observed in Klk5−/− compared to wildtype. Thus, KLK5 may represent a putative suppressor of vaginal cancer.


2017 ◽  
Author(s):  
Carmen Lía Murall ◽  
Robert Jackson ◽  
Ingeborg Zehbe ◽  
Nathalie Boulle ◽  
Michel Segondy ◽  
...  

Infections of stratified epithelia collectively represent a large burden on global health. Experimental models provide a means to understand how the cell dynamics themselves influence the outcomes of these infections. Mathematical approaches are needed to improve quantification and theoretical advancement of these complex systems. Here, we develop a general ecology-inspired model for stratified epithelial dynamics, which allows us to simulate infections and to estimate parameters that are difficult to measure with organotypic cell cultures. To explore how epithelial cell dynamics affect infection dynamics, we focus on two contrasting pathogens of the cervicovaginal epithelium:Chlamydia trachomatisand Human papillomaviruses. We find that key infection symptoms stem from differential interactions with the layers, while clearance and pathogen burden are bottom-up processes. Cell protective responses to infections (e.g. increased cell proliferation) generally lowered pathogen load but there were specific effects based on infection strategies. These generic responses by the epithelium, then, will have varying results depending on the pathogen’s infection strategy. Our modeling approach opens new perspectives for 3D tissue culture experimental systems of infections and, more generally, for developing and testing hypotheses related to infections of stratified epithelia.


2016 ◽  
Vol 397 (12) ◽  
pp. 1223-1228 ◽  
Author(s):  
Zela Keuylian ◽  
Alain Hovnanian

Abstract Protease regulation plays a crucial role in skin homeostasis and inflammation as revealed by the identification of loss-of-function mutations in SPINK5 (serine protease inhibitor of Kazal type 5) in Netherton sydrome (NS). SPINK5 encodes LEKTI (lympho-epithelial Kazal type related inhibitor), a multidomain serine protease inhibitor expressed in all stratified epithelia. Our laboratory has developed a number of murine models which have been instrumental in dissecting the pathogenesis of NS. This minireview discusses the major findings of these models and emphasizes the role of protease regulation, especially kallikrein-related peptidases in NS.


eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Mariko Yokouchi ◽  
Toru Atsugi ◽  
Mark van Logtestijn ◽  
Reiko J Tanaka ◽  
Mayumi Kajimura ◽  
...  

In multicellular organisms, cells adopt various shapes, from flattened sheets of endothelium to dendritic neurons, that allow the cells to function effectively. Here, we elucidated the unique shape of cells in the cornified stratified epithelia of the mammalian epidermis that allows them to achieve homeostasis of the tight junction (TJ) barrier. Using intimate in vivo 3D imaging, we found that the basic shape of TJ-bearing cells is a flattened Kelvin's tetrakaidecahedron (f-TKD), an optimal shape for filling space. In vivo live imaging further elucidated the dynamic replacement of TJs on the edges of f-TKD cells that enables the TJ-bearing cells to translocate across the TJ barrier. We propose a spatiotemporal orchestration model of f-TKD cell turnover, where in the classic context of 'form follows function', cell shape provides a fundamental basis for the barrier homeostasis and physical strength of cornified stratified epithelia.


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