An mRNA treatment for human skin rejuvenation. 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.

衰老以机体功能的渐进性衰退为核心特征，其部分成因是随时间不断累积的分子损伤。人类皮肤极易受到自然衰老（chronological aging）与紫外线光老化（UV photoaging）这类环境损伤的双重影响，随年龄增长会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自然衰老与光老化过程，并探究遗传与环境因素对衰老进程的调控作用。研究纳入了青年、中年及老年个体的皮肤样本，借此对比自然衰老与光老化的特征差异。

本研究采用单细胞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特征提供了关键参考。我们探究了衰老过程中表皮干细胞（epidermal stem cells）的增殖更新能力，并将研究范围拓展至成纤维细胞（fibroblasts）、毛囊细胞（hair follicles）与内皮细胞（endothelial cells）。通过分析角质形成细胞（keratinocytes）的衰老遗传调控网络，本研究鉴定出两个在衰老过程中表达发生显著改变的独特基因模块（gene modules）。

此外，本研究揭示，皮肤衰老过程中存在表皮角质形成细胞与真皮成纤维细胞间的相互作用，且通过配体-受体对（ligand-receptor pairs）分析发现，角质形成细胞与皮肤内多种其他细胞类型存在广泛的信号交流。诸如COL17A1-A1b1复合物这类相互作用，证实了角质形成细胞与成纤维细胞之间存在直接的调控关联，可促进胶原蛋白的生成。

最为关键的是，本研究鉴定出一个与皮肤衰老密切相关的关键基因MYO1，并以此为靶点开发了一种创新性的mRNA（messenger RNA）治疗方案，旨在通过靶向该基因实现皮肤年轻化。实验结果表明，该mRNA治疗方案可通过角质形成细胞-成纤维细胞间的信号交流，降低基底干细胞（basal stem cells）的衰老水平、促进其增殖，并增强成纤维细胞的胶原蛋白生成能力。该靶向MYO1的治疗方案经证实可通过调控细胞机制，有效逆转皮肤衰老。

研究整体设计：本研究针对23岁青年、53岁中年及85岁老年三类供体的手臂与背部皮肤样本，对比分析其皮肤转录组学（transcriptomics）特征。