Human skin rejuvenation via mRNA

Li, L.; Tang, Z.; Portillo, X.; Arora, R.; Yang, M.; Mintzer, E.; Han, P.; Zhang, Z.; Majewski, D. D.; Titelman, A. A.; Plesa, A. M.; Shadpour, M.; McNamee, S. M.; Zheng, Y.; Li, X.; Tam, J.; McGee, J.; Sol, S.; Boncimino, F.; Zhang, Y. S.; Mandinova, A.; Murphy, G. F.; Kupper, T. S.; Ma, S.; Church, G.

doi:10.1101/2024.11.12.623261

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bioRxiv · 10.1101/2024.11.12.623261

Human skin rejuvenation via mRNA

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Abstract

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. Detrimental structural and physiological changes caused by aging include epidermal thinning due to stem cell depletion and dermal atrophy associated with decreased collagen production. Here, we present a comprehensive single-cell atlas of skin aging, analyzing samples from young, middle-aged, and elderly individuals, including both sun-exposed and sun-protected areas. This atlas reveals age-related changes in cellular composition and function across various skin cell types, including epidermal stem cells, fibroblasts, hair follicles, and endothelial cells. Using our atlas, we have uncovered basal stem cells as a highly variable population across aging, more so than other skin cell populations, such as fibroblasts. In basal stem cells, we identified ATF3 as a novel regulator of skin aging. ATF3 is a transcriptional 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. After treatment with ATF3 mRNA, cell senescence decreased 25%, and we observed an over 20% increase in proliferation in treated basal stem cells. Importantly, we also found communication between keratinocytes and fibroblasts as a critical component of therapeutic interventions, with ATF3 mRNA rescue of basal cells significantly enhancing fibroblast collagen production by approximately 200%. Furthermore, we validated the efficacy of ATF3 mRNA treatment in ex vivo human skin and in vivo mouse models. In ex vivo human skin, microneedle-mediated delivery of ATF3 mRNA induced robust rejuvenation, expanding the basal stem-cell population and enhancing dermal ECM reconstruction. In a wound healing mouse model, ATF3 mRNA reduced scarring, demonstrating strong regenerative potential for reversing age-related skin decline. We conclude that ATF3 mRNA treatment effectively reverses the effects of skin aging by modulating specific cellular mechanisms, offering a novel, targeted approach to human skin rejuvenation.

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Li, L., Tang, Z., Portillo, X., Arora, R., Yang, M., Mintzer, E., Han, P., Zhang, Z., Majewski, D. D., Titelman, A. A., Plesa, A. M., Shadpour, M., McNamee, S. M., Zheng, Y., Li, X., Tam, J., McGee, J., Sol, S., Boncimino, F., Zhang, Y. S., Mandinova, A., Murphy, G. F., Kupper, T. S., Ma, S., Church, G.. 2024-11-13. Human skin rejuvenation via mRNA. https://doi.org/10.1101/2024.11.12.623261

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