ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells.
Si WangBoqiang HuZhichao DingYujiao DangJun WuDi LiXiaoling LiuBailong XiaoWeiqi ZhangRuotong RenJinghui LeiHuifang HuChang ChenPiu ChanDong LiJing QuFu-Chou TangGuang-Hui LiuPublished in: Cell discovery (2018)
Loss of organelle homeostasis is a hallmark of aging. However, it remains elusive how this occurs at gene expression level. 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 and human adipocytes, results in premature cellular aging, characteristic of loss of endomembrane homeostasis. Transcriptomic analyses uncover cell type-specific constitutive and stress-induced ATF6-regulated genes implicated in various layers of organelles' homeostasis regulation. FOS was characterized as a constitutive ATF6 responsive gene, downregulation of which contributes to hMSC aging. Our study unravels the first ATF6-regulated gene expression network related to homeostatic regulation of membrane organelles, and provides novel mechanistic insights into aging-associated attrition of human stem cells.
Keyphrases
- transcription factor
- endothelial cells
- gene expression
- mesenchymal stem cells
- stem cells
- induced pluripotent stem cells
- endoplasmic reticulum stress
- crispr cas
- stress induced
- pluripotent stem cells
- type diabetes
- cell proliferation
- signaling pathway
- oxidative stress
- skeletal muscle
- umbilical cord
- single cell
- drug delivery
- cell therapy
- metabolic syndrome
- genome editing
- rna seq