Functional stem cell aging dictated by skin tissue microenvironment

Organismal aging in mammals is manifested with architectural alteration and functional decline of multiple organs throughout the body. In aged skin, hairs are sparse, which has led to the hypothesis that the hair follicle stem cells (HFSCs) undergo epidermal differentiation during aging. Here, we employ single cell analysis to interrogate aging-related changes in the HFSCs. Unexpectedly, HFSCs maintain their lineage fidelity and show no signs of shifting to an epidermal fate. Despite maintaining lineage identity, HFSCs do show prevalent transcriptional changes in extracellular matrix genes. Of importance, these HFSC changes are accompanied by profound architectural perturbations in the aging stem cell niche. Upon surveying the dermis from young and aged skin, we also observe age-related changes in many non-epithelial cell types, including resident immune cells, sensory neurons, arrector pili muscles, and blood vessels – all of which have been previously associated with abilities to modulate hair follicle regeneration. Consistent with both intrinsic and extrinsic alterations in stem cell: niche communications, we find that in response to skin wounding, aged HFSCs repair the epidermis, but are defective in hair follicle regeneration. Intriguingly, whereas aged dermis cannot support young HFSCs, aged HFSCs can be rescued when supported by young dermis. Together, these findings favor a model where skin tissue microenvironment plays a dominant role in dictating the molecular properties and activities of HFSCs.哺乳动物的机体衰老，表现为全身多器官的结构改变与功能衰退。在衰老的皮肤中，毛发稀疏，这一现象催生了一项假说：毛囊干细胞（hair follicle stem cells, HFSCs）在衰老过程中会发生表皮分化。本研究采用单细胞分析技术，探究毛囊干细胞在衰老过程中的相关变化。出乎意料的是，毛囊干细胞维持了其细胞谱系保真度，并未出现向表皮细胞命运转化的迹象。尽管维持了谱系身份特征，毛囊干细胞在细胞外基质基因上却呈现出广泛的转录组变化。值得注意的是，这些毛囊干细胞的变化伴随衰老干细胞微环境出现了显著的结构扰动。通过对年轻与衰老皮肤的真皮层进行分析，我们还观察到多种非上皮细胞类型出现了衰老相关变化，包括驻留免疫细胞、感觉神经元、立毛肌与血管——此前已有研究表明，这些细胞类型均具备调控毛囊再生的能力。结合干细胞-微环境通讯的内在与外在改变这一背景，我们发现：在皮肤创伤应答过程中，衰老的毛囊干细胞能够修复表皮，但在毛囊再生过程中存在功能缺陷。有趣的是，尽管衰老的真皮层无法维持年轻毛囊干细胞的功能，但当衰老毛囊干细胞获得年轻真皮层的支持时，其功能可得到挽救。综上，本研究结果支持如下模型：皮肤组织微环境在决定毛囊干细胞的分子特性与活性方面发挥主导作用。

搜集汇总

背景与挑战

背景概述

该数据集聚焦于小鼠皮肤组织微环境对毛囊干细胞功能老化的影响，通过单细胞RNA-Seq和ATAC-seq技术分析年轻与年老样本的转录组和基因组变化。研究发现干细胞在衰老过程中保持谱系保真度，但转录组发生改变，且微环境对干细胞功能起主导作用，揭示了皮肤老化机制的关键因素。