Max Planck Institute for Biology of Ageing, Cologne, Germany.
Cologne Excellence Cluster for Stress Responses in Ageing-associated diseases (CECAD), University of Cologne, Cologne, Germany.
Nat Cell Biol. 2021 Jul;23(7):771-781. doi: 10.1038/s41556-021-00705-x. Epub 2021 Jul 8.
Tissue turnover requires activation and lineage commitment of tissue-resident stem cells (SCs). These processes are impacted by ageing, but the mechanisms remain unclear. Here, we addressed the mechanisms of ageing in murine hair follicle SCs (HFSCs) and observed a widespread reduction in chromatin accessibility in aged HFSCs, particularly at key self-renewal and differentiation genes, characterized by bivalent promoters occupied by active and repressive chromatin marks. Consistent with this, aged HFSCs showed reduced ability to activate bivalent genes for efficient self-renewal and differentiation. These defects were niche dependent as the transplantation of aged HFSCs into young recipients or synthetic niches restored SC functions. Mechanistically, the aged HFSC niche displayed widespread alterations in extracellular matrix composition and mechanics, resulting in mechanical stress and concomitant transcriptional repression to silence promoters. As a consequence, increasing basement membrane stiffness recapitulated age-related SC changes. These data identify niche mechanics as a central regulator of chromatin state, which, when altered, leads to age-dependent SC exhaustion.
组织更新需要组织驻留干细胞（SCs）的激活和谱系承诺。这些过程受年龄的影响，但机制尚不清楚。在这里，我们研究了小鼠毛囊干细胞（HFSCs）衰老的机制，观察到衰老的 HFSCs 中染色质可及性广泛降低，特别是在关键的自我更新和分化基因上，其特征是由活性和抑制性染色质标记占据的双价启动子。与此一致的是，衰老的 HFSCs 显示出激活双价基因以进行有效自我更新和分化的能力降低。这些缺陷依赖于龛位，因为将衰老的 HFSCs 移植到年轻的受体或合成龛位中可以恢复 SC 的功能。从机制上讲，衰老的 HFSC 龛位显示细胞外基质组成和力学的广泛改变，导致机械应激和伴随的转录抑制以沉默启动子。结果，增加基底膜硬度再现了与年龄相关的 SC 变化。这些数据表明龛位力学是染色质状态的一个核心调节剂，当它发生改变时，会导致与年龄相关的 SC 耗竭。
