Multitargeted Approach for the Optimization of Morphogenesis and Barrier Formation in Human Skin Equivalents.

Arnout Mieremet,Andreea Nadaban,Abdoelwaheb El Ghalbzouri,Walter A Boiten,Richard W J Helder,Joke A Bouwstra,Gert S Gooris

doi:10.3390/ijms22115790

Abstract

In vitro skin tissue engineering is challenging due to the manifold differences between the in vivo and in vitro conditions. Yet, three-dimensional (3D) human skin equivalents (HSEs) are able to mimic native human skin in many fundamental aspects. However, the epidermal lipid barrier formation, which is essential for the functionality of the skin barrier, remains compromised. Recently, HSEs with an improved lipid barrier formation were generated by (i) incorporating chitosan in the dermal collagen matrix, (ii) reducing the external oxygen level to 3%, and (iii) inhibiting the liver X receptor (LXR). In this study, we aimed to determine the synergic effects in full-thickness models (FTMs) with combinations of these factors as single-, double-, and triple-targeted optimization approaches. The collagen–chitosan FTM supplemented with the LXR inhibitor showed improved epidermal morphogenesis, an enhanced lipid composition, and a better lipid organization. Importantly, barrier functionality was improved in the corresponding approach. In conclusion, our leading optimization approach substantially improved the epidermal morphogenesis, barrier formation, and functionality in the FTM, which therefore better resembled native human skin.

Highlights

In-vitro-developed human skin equivalents (HSEs) replicate multiple critical aspects of in vivo skin biology due to the presence of a nourishing culture medium and a supportive micro-environment [1,2,3]
The optimization of in-vitro-developed full-thickness models (FTMs) using advanced single, double, and triple-targeted approaches resulted in a better resemblance of our FTMs to native human skin (NHS)
This concerned the epidermal morphogenesis after modification of the dermal extracellular matrix (ECM) by chitosan and the stratum corneum (SC) lipid composition after inhibition of the liver X receptor

Summary

Introduction

In-vitro-developed human skin equivalents (HSEs) replicate multiple critical aspects of in vivo skin biology due to the presence of a nourishing culture medium and a supportive micro-environment [1,2,3]. The stratum corneum (SC) is the main layer of the physical epidermal barrier [13] This outermost epidermal layer is composed of corneocytes that are embedded in a lipid matrix. CERs vary in head group architecture, resulting in the presence of at least 16 subclasses [18,19,20]. Both CERs and FFAs can differ in the number of carbons in the acyl chains and the degree of unsaturation, yielding a high diversity of lipid entities within the SC matrix. Variations in the lipid composition can induce changes in the lipid organization and functionality [21,22,23]

Objectives

Methods

Conclusion