Abstract
Darier disease (DD) is a dominantly inherited skin disorder. It is characterized by painful and malodourous plaques and papules on the skin of patients. The typical features of DD include: acantholysis and abnormal keratinization. These histological features are due to mutations in the gene, ATP2A2, which encodes the sarco/endoplasmic reticulum (ER) Ca2+-ATPase isoform 2 (SERCA2), a Ca2+-ATPase pump of the ER. This leads to malformation of the desmosomes and adherent junctions. Currently, there are no good in vitro models to study DD. An organoid is a collection of organ-specific cells that develops from stem cells or progenitors and is capable of recapitulating specific functions of the organ. Human epidermal organoids (HEOs) are obtained from the skin epidermis and have several advantages over 2D keratinocyte cultures. They have an in vivo-like complexity and architecture and have the ability to recapitulate the physiology of the epidermis. Exposure of normal keratinocytes to the SERCA2 inhibitor thapsigargin (TG) recapitulated the abnormalities observed in DD. HEOs exposed to TG showed acantholysis thus, recapitulating DD. In addition to this artificial, chemical-induced model, we also developed an HEO model derived from keratinocytes isolated from Darier patients’ lesional skin biopsies as well as an HEO model generated with CRISPR-Cas9-modified primary keratinocytes. These models can be used to screen for potential drugs to treat DD as well as study the pathomechanisms of the disease.
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