Impaired stemness in aging periodontal ligament stem cells is mediated by the progerin/endoplasmic reticulum stress/p53 axis

[Display omitted] •This study discovered the important role of ER stress activation and p53/p21 axis in decreased stemness of aging PDLSCs, and demonstrated that ATF6-mediated ER stress response was primarily involved in this regulatory effect.•This study found progerin accumulation in PDLSCs during the aging process resulted in ER stress, further activating the ATF6/p53/p21 axis, leading to decreased stemness of aging PDLSCs. Decreased periodontal ligament stem cells (PDLSCs) stemness is a key factor in age-related alveolar bone loss. Endoplasmic reticulum (ER) stress is closely related to age-related diseases and the mesenchymal stem cell (MSC) stemness. However, the role of ER stress in regulating the stemness of senescent PDLSCs and its potential mechanism remain unclear. To investigate the detailed effect and mechanism of ER stress on impaired stemness in old periodontal ligament stem cells (OPDLSCs). The level of ER stress of Young PDLSCs (YPDLSCs) and OPDLSCs were detected, and ER stress was regulated to observe its effect on PDLSCs stemness. The expression levels of ER stress sensors (protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), inositol requiring enzyme 1 (IRE1)) were upregulated in YPDLSCs and downregulated in OPDLSCs by transfection experiments to verify the detailed unfolded protein response (UPR) pathway. Mechanismly, the regulatory effect of UPR pathway on p53/p21 pathway was explored. Further study was performed to investigated the important role of progerin accumulation during aging process on ER stress, UPR and p53/p21 pathway. Decreased stemness and ER stress activation were found in OPDLSCs. ER stress activation resulted in decreased stemness of YPDLSCs, while ER stress inhibition rescued compromised stemness of OPDLSCs. Mechanismly, ATF6 pathway regulated the OPDLSC stemness via the p53/p21 signaling as confirmed by transfection assay. Further study showed that progerin was accumulated in PDLSCs and progerin overexpression could resulted in ER stress activation, activating the ATF6/p53/p21 axis, leading to decreased stemness of aging PDLSCs. Progerin accumulation during the aging process can lead to ER stress activation, which can suppress OPDLSC stemness via the ATF6/p53/p21 axis.