Tissue-scale tensional homeostasis in skin regulates structure and physiological function

Abstract

Tensional homeostasis is crucial for organ and tissue development, including the establishment of morphological and functional properties. Skin plays essential roles in waterproofing, cushioning and protecting deeper tissues by forming internal tension-distribution patterns, which involves aligning various cells, appendages and extracellular matrices (ECMs). The balance of traction force is thought to contribute to the formation of strong and pliable physical structures that maintain their integrity and flexibility. Here, by using a human skin equivalent (HSE), the horizontal tension-force balance of the dermal layer was found to clearly improve HSE characteristics, such as the physical relationship between cells and the ECM. The tension also promoted skin homeostasis through the activation of mechano-sensitive molecules such as ROCK and MRTF-A, and these results compared favourably to what was observed in tension-released models. Tension-induced HSE will contribute to analyze skin physiological functions regulated by tensional homeostasis as an alternative animal model.

Mechanical and Immunological Regulation in Wound Healing and Skin Reconstruction

“…Since the traditional Bell’s model induces tissue contraction due to suspension culture in the process of constructing a dermal equivalent [ 103 , 110 ], there is no tensional homeostasis in the living body, and it is not suitable for functional analysis of mechanical stress under physiological conditions ( Figure 5 c). Therefore, we have developed a tensional homeostatic skin model (THS model) that reproduces tensional homeostasis by mechanically fixing the tissue to a culture insert ( Figure 5 d) [ 18 ]. The THS model showed the same skin marker protein expression and skin barrier function as natural skin and general skin equivalents [ 18 ].…”

“…Therefore, we have developed a tensional homeostatic skin model (THS model) that reproduces tensional homeostasis by mechanically fixing the tissue to a culture insert ( Figure 5 d) [ 18 ]. The THS model showed the same skin marker protein expression and skin barrier function as natural skin and general skin equivalents [ 18 ]. As a result of detailed histological analysis, the orientation of fibroblasts and ECM in the tension direction, which is a characteristic of natural skin, was observed in the THS model, but the orientation was lost in Bell’s model [ 18 ].…”

“…The THS model showed the same skin marker protein expression and skin barrier function as natural skin and general skin equivalents [ 18 ]. As a result of detailed histological analysis, the orientation of fibroblasts and ECM in the tension direction, which is a characteristic of natural skin, was observed in the THS model, but the orientation was lost in Bell’s model [ 18 ]. Furthermore, as a result of skin functionality analysis, it was suggested that tensional homeostasis promotes epithelial turnover through epithelial–mesenchymal interaction by keratinocyte growth factor (KGF) [ 18 ].…”

“…As a result of detailed histological analysis, the orientation of fibroblasts and ECM in the tension direction, which is a characteristic of natural skin, was observed in the THS model, but the orientation was lost in Bell’s model [ 18 ]. Furthermore, as a result of skin functionality analysis, it was suggested that tensional homeostasis promotes epithelial turnover through epithelial–mesenchymal interaction by keratinocyte growth factor (KGF) [ 18 ]. In the THS model, it was confirmed that the ECM synthesis function was improved by the change in the mechano-sensing state due to the increase in integrin α2 expression and the activation of the mechanical stress signal by the nuclear translocation of MRTF-A [ 18 ].…”

“…Wound healing, which is affected by spatiotemporal cell–cell interactions and mechanobiological control, is an extremely complex physiological response, and it has been difficult to elucidate its detailed mechanisms under in vivo conditions. However, recent advances in tissue engineering technology have improved the reproduction of tissue structure and function in human skin equivalents, enabling in vitro analysis of partial wound healing mechanisms [ 16 , 17 , 18 ].…”