Improved organotypic skin model with reduced quantity of monounsaturated ceramides by inhibiting stearoyl-CoA desaturase-1

Richard W.J Helder,Jannik Rousel,Walter A Boiten,Gerrit S Gooris,Andreea Nadaban,Abdoelwaheb El Ghalbzouri,Joke A Bouwstra

doi:10.1016/j.bbalip.2021.158885

Abstract

Full thickness models (FTM) are 3D in vitro skin cultures that resemble the native human skin (NHS) to a great extent. However, the barrier function of these skin models is reduced. The skin barrier is located in the stratum corneum (SC) and consists of corneocytes embedded in a lipid matrix. In this matrix, deviations in the composition of the FTMs lipid matrix may contribute to the impaired skin barrier when compared to NHS. One of the most abundant changes in lipid composition is an increase in monounsaturated lipids for which stearoyl-CoA desaturase-1 (SCD-1) is responsible. To improve the SC lipid composition, we reduced SCD-1 activity during the generation of the FTMs. These FTMs were subsequently assessed on all major aspects, including epidermal homeostasis, lipid composition, lipid organization, and barrier functionality. We demonstrate that SCD-1 inhibition was successful and resulted in FTMs that better mimic the lipid composition of FTMs to NHS by a significant reduction in monounsaturated lipids. In conclusion, this study demonstrates an effective approach to normalize SC monounsaturated lipid concentration and may be a valuable tool in further optimizing the FTMs in future studies.

Highlights

Full thickness skin models (FTMs) are in vitro skin models that mimic native human skin (NHS) in many aspects and serve as a valuable tool to unravel biological processes in healthy and diseased skin [1]
The study was performed with inhibitor stearoyl-CoA desaturase-1 (SCD-1) concentration of 45 nM, which was supplemented to the culture medium
The most important modification was the reduction in the amount of muC ERs and monounsaturated free fatty acid (muFFA) in the stratum corneum (SC) of the FTMSCD-1, which resembles the lipid composition in NHS more closely

Summary

Introduction

Full thickness skin models (FTMs) are in vitro skin models that mimic native human skin (NHS) in many aspects and serve as a valuable tool to unravel biological processes in healthy and diseased skin [1]. In addi tion, FTMs serve as an excellent tool for the prediction of toxicity screenings and diffusion of novel compounds as an alternative for ani mal experiments [1,2,3,4]. The most important drawback is the reduced barrier function of the FTMs [5,6,7,8]. This limits the use of FTMs in the prediction of novel pharmaceutical compounds on their diffusion across the skin. There is an urgent need for a new generation of FTMs that mimic the NHS barrier properties more closely. To improve the skin barrier of the FTMs, normalization of the stratum corneum (SC) lipid composition is considered to be crucial [9,10,11]

Objectives

Methods

Results

Conclusion