Here, a CRISPR-Cas9-mediated LRRC8A gene knock-out was generated in human keratinocytes to investigate the function of LRRC8A during hypotonic stress response and differentiation. It was shown that LRRC8A is essential for VRAC activity and also contributes to regulatory volume decrease of HaCaT cells and primary keratinocytes. Additionally, hypotonic stimulation of HaCaT cells resulted in an increase of intracellular Caraisebox{1ex{scriptsize 2+ concentration, which enhanced VRAC activity and RVD. Interestingly, immunohistological staining showed preferential localization of LRRC8A in the basal layer of human native epidermis. Furthermore, it was shown that in the absence of LRRC8A not only proliferation of HaCaT cells was reduced but also expression of differentiation markers occurred earlier after induction of differentiation in 2D as well as in 3D reconstructed HaCaT epidermis equivalents. In contrast, barrier function of HaCaT epidermis equivalents was not altered in the absence of LRRC8A.
Taken together, LRRC8A is important in hypotonic stress response as well as keratinocyte proliferation and differentiation. It can be speculated that LRRC8A is another regulator for the transition from keratinocyte proliferation to differentiation and therefore important for epidermal homeostasis.
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