Reprogramming of epidermal keratinocytes by PITX1 transforms the cutaneous cellular landscape and promotes wound healing

Andrew M. Overmiller, Laboratory of Skin Biology, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Akihiko Uchiyama, Laboratory of Skin Biology, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Emma D. Hope, Laboratory of Skin Biology, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Subhashree Nayak, Laboratory of Skin Biology, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Christopher G. O'Neill, Laboratory of Skin Biology, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Kowser Hasneen, Laboratory of Skin Biology, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Yi-Wen Chen, Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington DC, United States of America.
Faiza Naz, Genomic Technology Section, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Stefania Dell'Orso, Genomic Technology Section, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Stephen R. Brooks, Biodata Mining and Discovery Section, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Kan Jiang, Biodata Mining and Discovery Section, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.
Maria I. Morasso, Laboratory of Skin Biology, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, United States of America.

Document Type

Journal Article

Publication Date

10-31-2024

Journal

JCI insight

DOI

10.1172/jci.insight.182844

Keywords

Bioinformatics; Dermatology; Mouse models; Skin

Abstract

Cutaneous wound healing is a slow process that often terminates with permanent scarring while oral wounds, in contrast, regenerate damage faster. Unique molecular networks in epidermal and oral epithelial keratinocytes contribute to the tissue-specific response to wounding, but key factors that establish those networks and how the keratinocytes interact with their cellular environment remain to be elucidated. The transcription factor PITX1 is highly expressed in the oral epithelium but is undetectable in cutaneous keratinocytes. To delineate if PITX1 contributes to oral keratinocyte identity, cell-cell interactions, and the improved wound healing capabilities, we ectopically expressed PITX1 in the epidermis of murine skin. Using comparative analysis of murine skin and oral (buccal) mucosa with scRNA-seq and spatial transcriptomics, we found that PITX1 expression enhances epidermal keratinocyte migration, proliferation, and alters differentiation to a quasi-oral keratinocyte state. PITX1+ keratinocytes reprogram intercellular communication between skin-resident cells to mirror buccal tissue while also stimulating the influx of neutrophils that establish a pro-inflammatory environment. Furthermore, PITX1+ skin heals significantly faster than control skin via increased keratinocyte activation and migration and a tunable inflammatory environment. These results illustrate that PITX1 programs oral keratinocyte identity and cellular interactions while also revealing critical downstream networks that promote wound closure.

Department

Genomics and Precision Medicine

Link to Full Text

Share

COinS