766 Co-expression of oral epithelial regenerative factors Sox2 and Pitx1 induces wound activation signature in skin keratinocytes

Abstract

Wounds in the oral mucosa heal more efficiently with little to no scarring in contrast to cutaneous wounds. By elucidating the intrinsic molecular differences distinguishing oral keratinocytes from skin keratinocytes, we can identify potential molecular factors that could be therapeutically targeted to improve re-epithelialization in the skin. We previously demonstrated that endogenous expression of the transcription factors Sox2 and Pitx1 in oral keratinocytes mediates a distinct transcriptional network important for the regenerative capacity of the oral mucosa. However, it is unclear if Sox2 and Pitx1 have overlapping regulatory roles in the endogenous oral regenerative transcriptional program. To determine if concomitant, ectopic expression of Sox2 and Pitx1 can induce wound-activation networks in the skin, we generated mice with conditional, basal expression of both Sox2 and Pitx1 in the skin (K14-Cre/LSL-Sox2 and K5-rtTA/Pitx1-Tet). RT-qPCR and immunofluorescence revealed that together, Sox2 and Pitx1 induce expression of wound activation markers (keratins 6a, 6b, 16, and 17) in healthy, unwounded epidermis. Analysis of RNA-sequencing data reveals that expression of differentially expressed genes correlates more strongly with expression of Sox2 than Pitx1. Gene Ontology analysis reveals that Sox2 expression alters epidermal cell processes such as keratinization, keratinocyte migration, and cornified envelope formation, while Pitx1 expression influences processes related to lipid metabolism. Altogether, these findings indicate that ectopic Sox2 and Pitx1 can induce wound-activation networks in murine skin which may promote a more efficient response to injury. Critically, the downstream pathways modulated by co-expression of Sox2 and Pitx1 may offer several potentially druggable targets to enhance cutaneous wound healing in the clinic.