Every morning the city wakes up and starts repairing itself: workers replace asphalt, painters coat facades, street sweepers haul away trash. You can picture skin as just such a city, where worker cells constantly renew the streets and buildings. But with age, the city hall, that is, the basal stem cells (the progenitor cells in the lower layer of the epidermis), begins to function worse: repair orders come less often, and the city falls into disrepair.
For a long time, scientists believed the main culprits in skin aging were fibroblasts, the cells that produce collagen and elastin, like bricks and mortar for walls. But when researchers built an atlas of 109,086 single skin cells from donors aged 23, 53, and 85, a different picture emerged. In basal stem cells, levels of the protein ATF3, which controls the genes of youth and stress resilience, drop sharply with age. This protein turned out to be the key official who gets fired from city hall as we grow older.
To bring the fired official back to the workplace, scientists created mRNA, a temporary instruction for the cell to produce the needed protein. It was delivered into cells, skin samples, and mice. In skin samples from a 62-year-old donor, the thickness of the basal layer increased 1.8-fold, and COL1A1 collagen rose 10-fold. In mice with wounds, ATF3 treatment reduced scarring. The effect on fibroblasts was indirect: the mRNA acted on keratinocytes, which then sent signals that made fibroblasts produce collagen. City hall began sending out orders again, and the workers returned to the construction site.
The work shifts the focus from fibroblasts to basal stem cells. Aging used to be described as a passive process, but now it has been shown that it can be reversed by restoring a single protein. This approach may work not only for skin but also for other organs that have stem cell niches. The next step is human trials to understand how long the effect of a single injection lasts. If all goes well, the city will be able to repair its own streets for many years to come.
To deliver the mRNA, they used a microneedle patch with needles 600 micrometers tall, thinner than a human hair. It painlessly pierces the stratum corneum and delivers the drug directly to living cells.
The idea of rejuvenation through stem cell activation brings to mind the film 'Paragraph 78' or the series 'Altered Carbon,' where bodies can be renewed. But here, instead of futuristic capsules, it's a simple mRNA injection that works on the principle of a vaccine.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.