Building barriers

ABSTRACT

Formation of tissue barriers starts in early development where it is critical for normal cell fate selection, differentiation and organogenesis. Barrier maintenance is critical to the ongoing function of organs during adulthood and aging. Dysfunctional tissue barrier formation and function at any stage of the organismal life cycle underlies many disease states.

KEYWORDS:

• aging
• Claudin
• development
• disease
• tissue barrier

Introduction

Being both robust and homeostatic is fundamental to organismal life. Tissue barriers contribute to homeostasis by helping to establish and maintain robust tissue and organ functionality throughout life. The notion of a tissue barrier and its importance is evident in the developing egg shortly after fertilization, where changes in cell shape and acquisition of polarization signal the initiation of stage- and tissue-specific formation of barriers that underlie morphogenesis and ultimately organ integrity and function. Our understanding of tissue barriers in both health and disease has grown enormously over the last two decades, as key molecular components of the barriers – most notably the tetraspan transmembrane protein family comprising Claudins – have been identified and their roles elucidated. To showcase some of these recent advances, I have recruited a number of contributors to this special issue and prompted them to cover diverse aspects of tissue barrier formation and function from development into adulthood and aging. Their coverage of not only normal healthy tissues and organs but various disease states is highly informative to robustness and homeostasis.

Claudins and tissue barriers

While the linkage between morphogenesis and formation of tissue barriers in embryonic development has been known for decades as has the importance of selective permeability barriers to organ function, the molecular basis of these exquisite tissue barriers was not fully appreciated until the discovery of the tetraspan transmembrane Claudin family of tight junction (TJ) proteins. Baumholtz et al¹ address the morphogenic events in epithelial tube formation and the essential role of Claudins in TJ formation, apical-basal cell polarity, cell adhesion and linking the TJ to the mechanical force-generating actin cytoskeleton. These coordinated morphogenetic events also underlie the crucial regulation of paracellular transport between epithelial cells.

One organ system that epitomizes our changing understanding is the epidermis, where early descriptions were built upon relatively static bricks and mortar-type protein-lipid barriers assembled in the terminally differentiated epidermis. Such models, while structurally detailed, did not provide an explanation for the fully functioning, dynamic and selective epidermal permeability barrier. Crawford and Dagnino² cover the development and maintenance of the adult epidermis and the unique aspects that control regulated inside-out and outside-in selective permeability in this system. They also cover studies linking physical and environmental challenges, for example UV irradiation, and certain diseases and conditions, for example, ichthyosis dermatitis, to TJ function and barrier integrity or dysfunction. Within this volume, examples from different epithelial tissue and organ systems underscore what we currently know about how genetic or environmental disruptions of functional tissue barriers in embryogenesis or adulthood lead to disease states spanning from chronic but minor or nonlife threatening, albeit impacting quality of life, to fatal.

As in the skin, the lungs are in direct contact with the environment through the tubular structure that constitutes the airway. The airway is exposed to foreign particles including infectious agents, allergens, and other substances that can damage the airway unless protected by a functional epithelial barrier in both the upper and lower airways. Yuksel and Turmel³ discuss characteristics of the lungs and respiratory system, starting from the beginning of life and extending into adulthood and aging, that determine the pathogenesis, clinical phenotype, and prognosis of respiratory diseases that result from barrier defects.

As may already be evident from these few examples, our understanding of tissue barriers has been enhanced greatly by the molecular exploration of normal development and diseases of different epithelial tissues. A case in point is the intestinal epithelium, an area of considerable interest since there are a number of human diseases involving dysfunctional barriers for which there is currently no cure. Nevertheless, the molecules identified in the intestinal TJs are providing a large number of promising therapeutic candidates. Using both gain of function and loss of junction approaches in mouse models, Claudin family members are being explored as described by Xing et al.,⁴ who has covered intestinal diseases such as entorocolitis, inflammatory bowel disease and the role of barrier dysfunction in colorectal cancers. These mouse models and human specimens have also highlighted the complexities inherent in not only understanding but controlling appropriate Claudin expression, including in situations where intrinsic compensatory mechanisms are activated in aberrant situations to try to rescue – not necessarily successfully – crucial barrier functions.

Intrinsic mechanisms to maintain the integrity of the barrier function are operative in an apparently wide variety of situations, including when apoptotic cells are present in tissues. Duszyc et al.,⁵ discuss how the phagocytosis and extrusion processes that occur as a result of apoptosis affect cell communication via ROCK and Rho cooperate to achieve smooth transitions and without much disruption to the barrier.

Barriers are not just reactive to environmental signals but are collaborative, as covered by Takiishi et al.,⁶ in relation to the gastrointestinal tract barrier and immune function. As already mentioned above for skin, the intestinal epithelial barrier is not a static physical barrier but rather strongly interacts with the gut microbiome and cells of the immune system. This powerful communication between epithelial cells, immune cells and microbiome shapes specific immune responses to antigens, balancing tolerance and effector immune functions. The authors review studies indicating that the composition of the gut microbiome affects immune system development and modulates immune mediators, which in turn affect the intestinal barrier. Dysbiosis may favor intestinal barrier disruption and could be related to increased susceptibility to certain diseases.

As aging populations increase across the globe, the prevention and treatment of age-associated conditions has become a rising healthcare priority, demanding novel approaches. the process of aging affects not only adult differentiated cells but also stem cell function which has implications for functional barriers, a topic covered by several authors. Parrish⁷ describes the impact of aging on various tissues, including the epidermis, lung, gastrointestinal tract and kidney. Delaney and Campbell⁸ cover aging-related changes in the blood-brain barrier and how these contribute to the manifestation of disease in the nervous and vascular systems. The blood-brain barrier is a necessity for cerebral homeostasis and response to environmental insult, thus loss in functionality with age creates opportunities for disease to arise in the aged brain. Aging-related changes in the blood-brain barrier are also closely linked to the aging cardiovascular system and age-associated diseases such as stroke, atherosclerosis and cardiac arrest. Changes in the highly specialized cerebral vasculature may similarly drive neurodegenerative and neuropsychiatric disease. Understanding how the barrier is developed and maintained throughout the earlier years of adult life can identify key processes that may have beneficial applications in the restoration of function of the aged brains.

Conclusions

As already noted, as knowledge of different tissue barriers has grown, comparisons across tissues and organs have helped accelerate our understanding of the importance of the Claudin profile and the role played by specific members of the Claudin family to highly selective and tissue-specific barriers. Furthermore, how genetic aberrations and the dynamism and plasticity of Claudin expression contributes to disease initiation and establishment are topics covered by essentially all the reviews in this volume. In spite of these advances, these chapters collectively also point to the fact that much remains to be learned about regulation of Claudin expression in health and disease if we are all to achieve the homeostasis that underlies robustness.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.