Molecular Reorganization during the Formation of the Human Skin Barrier Studied In Situ

Abstract

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Acidic pH Is Required for the Multilamellar Assembly of Skin Barrier Lipids In Vitro

“…The driving mechanism for this transition is likely a hydrophobic mismatch between rigid Cer acyl chains and mobile Cer sphingosine chains that makes Cer hairpin conformation energetically unfavorable (Engberg et al, 2020). Putatively, this mismatch may drive membrane remodeling into multilayers where Cers are in an extended conformation with clustered mobile and rigid chains, which is consistent with the model suggested very recently (Narangifard et al, 2020).…”

“…This structure was stable for at least 2 weeks. This height difference is intriguingly close to the repeat distance of lipid lamellae in human SC (d = 12 -13 nm (Bouwstra et al, 1992;Madison et al, 1987) or 11 nm (Iwai et al, 2012;Narangifard et al, 2020)). Notably, a similar experiment with purified human SC Cers mixed with FFAs/Chol/Chol sulfate at a 1:1:1:0.13 molar ratio showed neither the plateau in the isotherms nor multilayers (data not shown) pointing at an important role of the full SC lipid spectrum (likely FFAs) in this event.…”

“…To fill this crucial gap in our understanding of the origin of the skin barrier, we studied the behavior of monolayers and multilayers of either synthetic SC lipids or isolated human SC lipids at pH 5.5 and 7.4. The lipid monolayers on an aqueous subphase reasonably mimic one membrane leaflet (2D lipid arrangement) at the stratum granulosum/SC interface without assuming whether the lipids come from lamellar bodies (Feingold and Elias, 2014) or the recently suggested cubic phase (Narangifard et al, 2018). Importantly, a monolayer may undergo a 2D-3D lipid transition (Lee, 2008) if the lipids choose to do so, a transition similar to what is expected from the SC lipids during the formation of the permeability barrier.…”

Soft X-ray microscopy for probing of topical tacrolimus delivery via micelles

“…This shows a constant background in the viable epidermis for all micrographs (see Figure 2(e)-(h)), which is not considered for the present analysis. We assume that these highlighted structures are due to carbon-rich moieties in the upper part of the viable epidermis, which can be assigned to granular and lamellar patterns according to electron microscopy studies [34,35]. Note that these occur only in the stratum granulosum and below, but not in the stratum corneum, yielding a chemical contrast, which is similar to the topically applied substances under study.…”

The Skin's Barrier: A Cryo-EM Based Overview of its Architecture and Stepwise Formation

“…In our laboratory, we have applied cryo-EM of vitreous sections (CEMOVIS) to elucidate in situ the molecular organization and the formation process of the skin's barrier structure (den Hollander et al, 2016;Iwai et al, 2012;Lundborg et al, 2018a;Narangifard et al, 2021Narangifard et al, , 2018Wennberg et al, 2018). In cryo-EM, the tissue is preserved down to the molecular level at near-native conditions (Al-Amoudi et al, 2004;Dubochet et al, 1988).…”