Skin rejuvenation via mRNA

mRNA-based therapeutic approach targeting ATF3 to reverse skin aging

Aging is characterized by a gradual decline in function, partly due to accumulated molecular damage. Human skin undergoes both chronological aging and environmental degradation, particularly UV-induced photoaging. We developed a comprehensive single-cell atlas of skin aging and identified an mRNA-based treatment to mitigate the effects of skin aging.

Single-Cell Atlas

We analyzed samples from young, middle-aged, and elderly individuals, including both sun-exposed and sun-protected areas. This atlas reveals age-related cellular composition and function changes across various skin cell types, including epidermal stem cells, fibroblasts, hair follicles, and endothelial cells. We identified basal stem cells as a highly variable population across aging, more so than other skin cell populations such as fibroblasts.

ATF3 Discovery

In basal stem cells, we identified ATF3 as a novel regulator of skin aging. ATF3 is a transcription factor for genes involved in the aging process, with its expression reduced by 20% during aging. Based on this discovery, we developed an innovative mRNA-based treatment to mitigate the effects of skin aging.

Cell senescence decreased 25% in skin cells treated with ATF3 mRNA
Over 20% increase in proliferation in treated basal stem cells
ATF3 rescue of basal cells significantly enhanced fibroblast collagen production by approximately 200%

Keratinocyte-Fibroblast Crosstalk

We found crosstalk between keratinocytes and fibroblasts as a critical component of therapeutic interventions. ATF3 expression in basal stem cells stimulates collagen production in fibroblasts through ATF3-regulated factors, demonstrating that key regulatory genes in one cell type can influence both epidermal and dermal layers.

Collaborators

This work was conducted with researchers from Harvard Medical School, Wyss Institute, Brigham and Women's Hospital, MIT, and Massachusetts General Hospital, in collaboration with George Church's lab. Key collaborators include Li Li, Sai Ma, and Anna Mandinova.

Data Availability

Single-cell RNA sequencing data are available at GEO (GSE274955).