Bicellular Tight Junctions and Wound Healing

Abstract

Bicellular tight junctions (TJs) are intercellular junctions comprised of a variety of transmembrane proteins including occludin, claudins, and junctional adhesion molecules (JAMs) as well as intracellular scaffold proteins such as zonula occludens (ZOs). TJs are functional, intercellular structures that form a barrier between adjacent cells, which constantly seals and unseals to control the paracellular passage of molecules. They are primarily present in the epithelial and endothelial cells of all tissues and organs. In addition to their well-recognized roles in maintaining cell polarity and barrier functions, TJs are important regulators of signal transduction, which modulates cell proliferation, migration, and differentiation, as well as some components of the immune response and homeostasis. A vast breadth of research data is available on TJs, but little has been done to decipher their specific roles in wound healing, despite their primary distribution in epithelial and endothelial cells, which are essential contributors to the wound healing process. Some data exists to indicate that a better understanding of the functions and significance of TJs in healing wounds may prove crucial for future improvements in wound healing research and therapy. Specifically, recent studies demonstrate that occludin and claudin-1, which are two TJ component proteins, are present in migrating epithelial cells at the wound edge but are absent in chronic wounds. This indicates that functional TJs may be critical for effective wound healing. A tremendous amount of work is needed to investigate their roles in barrier function, re-epithelialization, angiogenesis, scar formation, and in the interactions between epithelial cells, endothelial cells, and immune cells both in the acute wound healing process and in non-healing wounds. A more thorough understanding of TJs in wound healing may shed new light on potential research targets and reveal novel strategies to enhance tissue regeneration and improve wound repair.

Polarity and epithelial-mesenchymal transition of retinal pigment epithelial cells in proliferative vitreoretinopathy

“… Feng et al (2019) demonstrated that during EMT, the breakdown of TJs resulting from loss of claudin-1 causes ARPE-19 cells to lose their epithelial phenotype and transform into fibroblasts, promoting the development of PVR. TJs are involved in the regulation of signaling pathways that govern various cellular functions such as proliferation, migration, and differentiation ( Bhat et al, 2018 ; Shi et al, 2018 ; Sluysmans et al, 2017 ). Vietor et al (2001) found that decreased amounts of occludin can cause up-regulation and translocation of the adhesion junction protein β-catenin, which interacts with the transcription factor lymphoid enhancer-binding factor (LEF)/T cell factor (TCF) in the nucleus, leading to a loss of the polarized epithelial phenotype in EpH4 cells.…”

“…ZOs, adaptor proteins within the TJ complex, exhibit dual localization at TJs and in the nucleus. Under injury or stress, the disruption of TJs increases ZO-2 nuclear accumulation, driving its interaction with transcription factors, and inducing MDCK epithelial cell proliferation ( Islas et al, 2002 ; Shi et al, 2018 ; Traweger et al, 2003 ). In differentiated RPE cells, the interaction between ZO-1 with ZO-1-associated nucleic acid-binding protein (ZONAB) maintains cell–cell contact by sequestering ZONAB at the TJ or in the cytoplasm, maintaining cells dormancy.…”

The Dynamics of the Skin’s Immune System

“…Junctional adhesion molecules (JAMs), claudins, zonula occludins-1 (ZO-1), and occludins are found in epidermal layers. Claudin-1, claudin-7, and JAM-A are found in all layers of the human epidermis [16], while claudin-1, claudin-12, and JAM-A are ubiquitous in murine epidermal layers [17,18]. The importance of tight junction proteins in skin function was demonstrated by Furuse et al, who showed that deletion of claudin-1 in mice led to death shortly after birth as a result of cutaneous defects ultimately leading to significant loss of fluids [19].…”

Differential Expression and Function of Bicellular Tight Junctions in Skin and Oral Wound Healing

“…However, we do not know how the differential expression of these identified TJ molecules contributes to the different healing phenotypes in skin and oral mucosa. We speculate that these TJ molecules could be differentially regulated in relation to their roles in barrier function, proliferation, or migration of keratinocytes, as well as their roles in innate immunity in the skin and oral mucosa [26]. Further studies are needed to elucidate why there is tissue specificity and the function of these tight junction genes in the wound healing setting.…”

“…In a guinea pig oral hard palate wound model, TJs were absent or fragmentary in the wound epithelium [25]. Multiple studies now suggest that TJs play a critical role in the healing of epithelial tissues (for a comprehensive review of TJ function in wound healing, see [26]).…”