Mechanisms that play a role in the maintenance of the calcium gradient in the epidermis

Cornelissen, LH Lisette; Oomens, Cwj Cees; Huyghe, Jmrj Jacques; Baaijens, Fpt Frank

doi:10.1111/j.1600-0846.2007.00239.x

Cited by 19 publications

(13 citation statements)

References 30 publications

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“…Our model shows that the gradient can only persist when the epidermal barrier locally restricts both calcium diffusion and transport in the SG and SS. Analogous results were found in mathematical continuum models investigating the calcium gradient in the epidermis4950. Thus, computational modelling highlights that TEWL alone cannot account for the calcium gradient unless coupled to the epidermal barrier.…”

Section: Discussionsupporting

confidence: 57%

A 3D self-organizing multicellular epidermis model of barrier formation and hydration with realistic cell morphology based on EPISIM

Sütterlin

Tsingos

Bensaci

et al. 2017

Sci Rep

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The epidermis and the stratum corneum (SC) as its outermost layer have evolved to protect the body from evaporative water loss to the environment. To morphologically represent the extremely flattened cells of the SC - and thereby the epidermal barrier - in a multicellular computational model, we developed a 3D biomechanical model (BM) based on ellipsoid cell shapes. We integrated the BM in the multicellular modelling and simulation platform EPISIM. We created a cell behavioural model (CBM) with EPISIM encompassing regulatory feedback loops between the epidermal barrier, water loss to the environment, and water and calcium flow within the tissue. This CBM allows a small number of stem cells to initiate self-organizing epidermal stratification, yielding the spontaneous emergence of water and calcium gradients comparable to experimental data. We find that the 3D in silico epidermis attains homeostasis most quickly at high ambient humidity, and once in homeostasis the epidermal barrier robustly buffers changes in humidity. Our model yields an in silico epidermis with a previously unattained realistic morphology, whose cell neighbour topology is validated with experimental data obtained from in vivo images. This work paves the way to computationally investigate how an impaired SC barrier precipitates disease.

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Section: Discussionsupporting

confidence: 57%

A 3D self-organizing multicellular epidermis model of barrier formation and hydration with realistic cell morphology based on EPISIM

Sütterlin

Tsingos

Bensaci

et al. 2017

Sci Rep

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“…Several experimental (Celli et al, 2010; Jungman et al, 2012; Mauro et al, 1998; Menon et al, 1992; Tsutsumi et al, 2009) and computational approaches (Adams et al, 2012, 2015; Cornelissen et al, 2007; Denda et al, 2014) have been used to model or measure Ca 2+ fluxes in epidermis. While initial studies using fixed and sectioned tissue (Mauro et al, 1998; Menon et al, 1992) showed that after acute barrier perturbation, Ca 2+ drops in the viable layers and then recovers as the barrier recovers, a more recent study (Behne et al, 2011) reported a moderate increase in intracellular and extracellular calcium concentration as soon as 30 minutes after barrier perturbation by acetone lipid extraction in hairless mice.…”

Section: Discussionmentioning

confidence: 99%

“…This Ca 2+ gradient depends on a competent epidermal barrier (Mauro et al, 1998; Menon and Elias, 1991; Menon et al, 1994), which in turn is formed by keratinocyte Ca 2+ uptake, release, and influx (Feingold and Denda, 2012; Hu et al, 2000; Man et al, 1997). Studies from our group (Celli et al, 2010) and others (Adams et al, 2012; Cornelissen et al, 2007; Denda et al, 2012) have identified intracellular, rather than extracellular, calcium stores as the main components of the epidermal calcium gradient, and shown that ER Ca 2+ release alone can control barrier repair processes (Celli et al, 2011). …”

Section: Introductionmentioning

confidence: 97%

Endoplasmic Reticulum Calcium Regulates Epidermal Barrier Response and Desmosomal Structure

Celli

Crumrine

Meyer

et al. 2016

Journal of Investigative Dermatology

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Ca2+ fluxes direct keratinocyte differentiation, cell-to-cell adhesion, migration, and epidermal barrier homeostasis. We previously showed that intracellular Ca2+ stores constitute a major portion of the calcium gradient especially in the stratum granulosum. Loss of the calcium gradient triggers epidermal barrier homeostatic responses. In this report, using unfixed ex vivo epidermis and human epidermal equivalents we show that endoplasmic reticulum (ER) Ca2+ is released in response to barrier perturbation, and that this release constitutes the major shift in epidermal Ca2+ seen after barrier perturbation. We find that ER Ca2+ release correlates with a transient increase in extracellular Ca2+. Lastly, we show that ER calcium release resulting from barrier perturbation triggers transient desmosomal remodeling, seen as an increase in extracellular space and a loss of the desmosomal intercellular midline. Topical application of thapsigargin, which inhibits the ER Ca2+ ATPase activity without compromising barrier integrity, also leads to desmosomal remodeling and loss of the midline structure. These experiments establish the ER Ca2+ store as a master regulator of the Ca2+ gradient response to epidermal barrier perturbation, and suggest that ER Ca2+ homeostasis also modulates normal desmosomal reorganization, both at rest and after acute barrier perturbation.

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“…This is especially important since the rapid secretion by keratinocytes of lamellar bodies (the precursor to lipids that form the “mortar” component of the SC barrier) following barrier disruption is primarily controlled by calcium ions in the SG [ 13 ]. Whilst our conceptual model provides a feasible explanation for the formation of the calcium profile, especially as model parameters were obtained from experimental data, we cannot rule out the possibility of the contribution to this profile from other factors, such as the lipid barrier [ 78 ], electrophoresis [ 81 ], or binding of calcium to molecules such as profilaggrin [ 82 ]. In addition, if the factors that contribute substantially to the epidermal calcium profile occur on length scales of cells or smaller, our mathematical treatment of the epidermis as a porous medium may not be appropriate, and individual cell-based models (e.g.…”

Section: Discussionmentioning

confidence: 99%

Towards a Quantitative Theory of Epidermal Calcium Profile Formation in Unwounded Skin

2015

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We propose and mathematically examine a theory of calcium profile formation in unwounded mammalian epidermis based on: changes in keratinocyte proliferation, fluid and calcium exchange with the extracellular fluid during these cells’ passage through the epidermal sublayers, and the barrier functions of both the stratum corneum and tight junctions localised in the stratum granulosum. Using this theory, we develop a mathematical model that predicts epidermal sublayer transit times, partitioning of the epidermal calcium gradient between intracellular and extracellular domains, and the permeability of the tight junction barrier to calcium ions. Comparison of our model’s predictions of epidermal transit times with experimental data indicates that keratinocytes lose at least 87% of their volume during their disintegration to become corneocytes. Intracellular calcium is suggested as the main contributor to the epidermal calcium gradient, with its distribution actively regulated by a phenotypic switch in calcium exchange between keratinocytes and extracellular fluid present at the boundary between the stratum spinosum and the stratum granulosum. Formation of the extracellular calcium distribution, which rises in concentration through the stratum granulosum towards the skin surface, is attributed to a tight junction barrier in this sublayer possessing permeability to calcium ions that is less than 15 nm s−1 in human epidermis and less than 37 nm s−1 in murine epidermis. Future experimental work may refine the presented theory and reduce the mathematical uncertainty present in the model predictions.

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Mechanisms that play a role in the maintenance of the calcium gradient in the epidermis

Cited by 19 publications

References 30 publications

A 3D self-organizing multicellular epidermis model of barrier formation and hydration with realistic cell morphology based on EPISIM

A 3D self-organizing multicellular epidermis model of barrier formation and hydration with realistic cell morphology based on EPISIM

Endoplasmic Reticulum Calcium Regulates Epidermal Barrier Response and Desmosomal Structure

Towards a Quantitative Theory of Epidermal Calcium Profile Formation in Unwounded Skin

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