皮肤衰老与再生的机制和调控Mir-31 Rawdata

前期研究提示毛囊干细胞在衰老过程中最终耗竭消失，导致毛囊和皮脂腺萎缩，但其中的机制并不完全清楚，也缺乏有临床潜力的干预途径。我们发现小鼠毛囊干细胞的自然衰老和辐射早衰过程中存在显著的miR-31表达上调，源于衰老过程中累积的DNA损伤或物理损伤。利用小鼠模型和谱系追踪技术，发现miR-31通过下调其靶基因Clock来激活毛囊干细胞中的MAPK/ERK信号通路，进而驱使这些干细胞以类似于愈伤反应的形式向表皮异常转分化并耗竭。在此基础上，揭示了两种拮抗皮肤毛囊衰老的新途径：靶向抑制miR-31或MAPK/ERK。一方面，条件性敲除小鼠毛囊干细胞中的miR-31导致毛囊“冻龄”，显著延缓自然衰老过程中的毛囊萎缩与脱发，且无明显副作用。另一方面，以临床抗癌药曲美替尼为代表的MAPK/ERK抑制剂“老药新用”（口服或涂抹），能高效拮抗电离辐射导致的毛囊萎缩与皮肤愈伤缺陷，且无明显副作用。利用临床样本与人类细胞模型，发现miR-31上调与人表皮和毛囊的衰老均密切相关，且其下游机制在人表皮细胞中保守，提示其可能在人表皮衰老中也发挥了重要作用。

Previous studies have suggested that hair follicle stem cells (HFSCs) are ultimately exhausted and lost during aging, leading to atrophy of hair follicles and sebaceous glands. However, the underlying mechanisms remain incompletely understood, and there is a lack of clinically promising intervention strategies. We found that miR-31 expression is significantly upregulated in both naturally aged and radiation-induced prematurely aged hair follicle stem cells of mice, which stems from accumulated DNA damage or physical insults during the aging process. Using mouse models and lineage tracing technology, we discovered that miR-31 activates the MAPK/ERK signaling pathway in HFSCs by downregulating its target gene Clock, thereby driving these stem cells to undergo aberrant transdifferentiation into epidermal cells in a manner similar to wound healing responses and leading to their exhaustion. Building on these findings, we identified two novel approaches to antagonize skin and hair follicle aging: targeted inhibition of miR-31 or the MAPK/ERK pathway. On one hand, conditional knockout of miR-31 in mouse HFSCs results in 'age-freezing' of hair follicles, significantly delaying hair follicle atrophy and hair loss during natural aging, with no obvious adverse side effects. On the other hand, repurposing MAPK/ERK inhibitors represented by the clinical anticancer drug trametinib (administered orally or topically) can efficiently antagonize ionizing radiation-induced hair follicle atrophy and skin wound healing defects, with no obvious adverse side effects. Using clinical samples and human cell models, we found that upregulation of miR-31 is closely associated with aging of both human epidermis and hair follicles, and its downstream mechanism is conserved in human epidermal cells, suggesting that it may also play an important role in human epidermal aging.

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背景概述

该数据集聚焦于皮肤衰老与再生的机制研究，特别是miR-31在小鼠毛囊干细胞衰老过程中的作用。数据集包含20个小鼠皮肤样本的原始测序数据（RNA-seq和miRNA-Seq），涉及自然衰老和辐射诱导早衰模型，用于探索miR-31通过MAPK/ERK信号通路驱动干细胞耗竭的分子机制。