ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells

Loss of organelle homeostasis is a hallmark of aging. However, it remains elusive how this occurs at transcriptional levels. Here, we report that human mesenchymal stem cell (hMSC) aging is associated with dysfunction of double-membrane organelles and downregulation of transcription factor ATF6. CRISPR/Cas9-mediated inactivation of ATF6 in hMSCs, not in human embryonic stem cells (hESCs), resulted in premature cellular aging, characteristic of loss of endomembrane homeostasis. Comparative transcriptomic analyses in hMSCs identify 145 constitutive and 112 tunicamycin-induced ATF6-regulated genes implicated in different layers of cellular homeostasis regulation. Notably, FOS was identified as one of the constitutive ATF6 responsive genes, downregulation of which contributes to accelerated hMSC senescence. Our study identifies a novel transcriptional program related to homeostatic regulation of membrane organelles, and provides mechanistic insights into aging-associated attrition of human stem cells.

细胞器稳态失衡是衰老的标志性特征。然而，其转录层面的具体调控机制仍不明晰。本研究发现，人间充质干细胞（human mesenchymal stem cell, hMSC）的衰老过程与双层膜细胞器功能异常以及转录因子ATF6的表达下调密切相关。在hMSCs中通过CRISPR/Cas9介导灭活ATF6，而非人胚胎干细胞（human embryonic stem cells, hESCs），可诱导细胞过早衰老，其表型特征与内膜稳态丧失一致。对hMSCs开展的比较转录组分析显示，共有145个组成型调控基因与112个衣霉素（tunicamycin）诱导基因受ATF6调控，这些基因参与细胞稳态调控的不同层级。值得注意的是，FOS被鉴定为组成型ATF6应答基因之一，其表达下调会加速hMSC的衰老进程。本研究揭示了一条与膜细胞器稳态调控相关的全新转录程序，为衰老相关的人类干细胞耗竭提供了机制层面的新见解。