An mRNA treatment for human skin rejuvenation

Aging is characterized by a gradual decline in function, partly due to molecular damage that accumulates over time. Human skin is highly susceptible to both chronological aging and environmental damage in the form of UV photoaging. This results in detrimental structural and physiological changes with age. In this study we sought to comprehensively address both chronological and photoaging at the single-cell level, and to explore genetic and environmental factors, revealing their influences on the aging process. We included samples from young, middle-aged, and old individuals, and with these samples, we compared chronological aging and photoaging. Utilizing single-cell RNA sequencing, we created a comprehensive human skin cell atlas, that offers insights into the cellular composition and functions. We investigated the renewal ability of epidermis stem cells as they age and extended the study to fibroblasts, hair follicles, and endothelial cells. Examining the genetic landscape of aging in keratinocytes, we identified two distinct "gene modules" with altered gene expression during aging. Furthermore, we uncovered that skin aging involves interactions between epidermal keratinocytes and dermal fibroblasts, as well as extensive communication of keratinocytes with various other skin cell types as revealed through ligand-receptor pairs. Interactions, such as COL17A1-A1b1complex, highlighted a direct link between keratinocytes and fibroblast stimulation for collagen production. Most importantly, A key gene, MYO1, associated with skin aging was identified, leading to the development of an innovative mRNA treatment aimed at promoting skin rejuvenation by targeting this gene. Experimental results demonstrated that the mRNA treatment reduces basal stem cell senescence, increases basal stem cell proliferation, and enhances collagen production in fibroblasts via keratinocyte-fibroblast communication. The MYO1-targeted treatment is validated as an effective strategy for reversing skin aging by targeting cellular mechanisms. Overall design: This study compared skin transcriptomics between skin samples from the arm and back of donors at three ages: young individuals aged 23, middle-aged individuals aged 53, and elderly individuals aged 85.

衰老以功能的渐进性衰退为特征，其部分诱因是随时间累积的分子损伤。人类皮肤极易受到时序衰老（chronological aging）与紫外线光老化（UV photoaging）两种形式的损伤影响，并随年龄增长出现有害的结构与生理变化。本研究旨在从单细胞层面全面解析时序衰老与光老化，并探究遗传与环境因素，揭示其对衰老进程的影响。我们收集了青年、中年及老年个体的皮肤样本，并以此对比分析了时序衰老与光老化的差异。本研究借助单细胞RNA测序（single-cell RNA sequencing）技术构建了全面的人类皮肤细胞图谱，为解析皮肤细胞的组成与功能提供了重要视角。我们探究了表皮干细胞随衰老发生的更新能力变化，并将研究范围拓展至成纤维细胞、毛囊细胞及内皮细胞。通过分析角质形成细胞衰老的遗传表达特征，我们鉴定出两个在衰老过程中基因表达发生显著失调的独特基因模块（"gene modules"）。此外，我们发现皮肤衰老涉及表皮角质形成细胞与真皮成纤维细胞之间的相互作用，同时通过配体-受体对（"ligand-receptor pairs"）分析揭示了角质形成细胞与多种其他皮肤细胞类型间的广泛通讯。诸如COL17A1-A1b1复合物的细胞互作，揭示了角质形成细胞与成纤维细胞之间的直接调控关联，可驱动胶原蛋白的合成。最为重要的是，我们鉴定出一个与皮肤衰老相关的关键基因MYO1，并以此为靶点开发了一种创新性的mRNA治疗方案，旨在促进皮肤年轻化。实验结果表明，该mRNA治疗方案可通过角质形成细胞-成纤维细胞通讯通路，降低基底干细胞的衰老程度、增强其增殖能力，并促进成纤维细胞的胶原蛋白合成。靶向MYO1的治疗方案经验证为一种通过调控细胞机制逆转皮肤衰老的有效策略。研究整体设计：本研究对三名不同年龄段供者（23岁青年、53岁中年及85岁老年）的手臂与背部皮肤样本的转录组进行了对比分析。