Robin Neustein Laboratory of Mammalian Development and Cell Biology, The Rockefeller University, New York, NY 10065;
Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5339-5350. doi: 10.1073/pnas.1901720117. Epub 2020 Feb 24.
Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.
衰老是指生物体多个器官的结构改变和功能衰退。在哺乳动物中，老化的皮肤伴随着毛发循环明显减少和秃头的出现，这促使研究人员提出毛囊干细胞（HFSCs）在衰老过程中要么丢失、分化，要么转变为表皮命运。在这里，我们采用单细胞 RNA 测序来探究 HFSCs 与衰老相关的变化。令人惊讶的是，尽管数量减少，但衰老的 HFSCs 仍然存在，保持其身份，并且没有明显向表皮命运转变的迹象。然而，它们确实表现出普遍的转录变化，特别是在细胞外基质基因中，这伴随着衰老 SC 龛位的深刻结构扰动。此外，许多非上皮细胞类型，包括常驻免疫细胞、感觉神经元和立毛肌，都发生了明显的与年龄相关的变化。这些 SC 龛位成分中的每一个都被证明会影响 HF 的再生。当我们进行已知会动员年轻 HFSCs 离开其龛位并再生 HF 的皮肤损伤时，我们发现衰老的皮肤在这方面存在缺陷。然而，有趣的是，在体内移植实验中，当支持年轻真皮时，衰老的 HFSCs 可以再生 HF，而当与衰老真皮结合时，年轻的 HFSCs 则无法再生 HF。总之，我们的研究结果强调了 SC：龛位相互作用的重要性，并支持了这样一种模式，即龛位微环境的年轻程度在决定其 SC 和组织健康和适应性方面起着主导作用。
