FTO Suppresses Dental Pulp Stem Cell Senescence by Destabilizing NOLC1 mRNA

TL;DR

This study shows that the FTO protein prevents dental pulp stem cell aging by reducing the stability of NOLC1 mRNA, offering new insights for regenerative medicine.

Contribution

The novel finding is that FTO suppresses DPSC senescence by destabilizing NOLC1 mRNA through m6A modification.

Findings

FTO expression decreases during DPSC senescence and its depletion accelerates senescence and increases ROS.

NOLC1 is a novel FTO target whose upregulation promotes DPSC senescence via nucleolar stress and p53 accumulation.

NOLC1 knockdown partially rescues FTO deficiency-induced DPSC senescence.

Abstract

Cellular senescence is an intricate process that severely restricts stem cell function. The N6-methyladenosine (m6A) eraser, fat mass and obesity-associated (FTO) protein control several aspects of stem cell fate, including differentiation, self-renewal, and senescence. However, the role of FTO in dental pulp stem cell (DPSC) senescence has not yet been elucidated. This study aimed to explore the role of FTO in DPSC senescence. FTO expression decreases during DPSC senescence. FTO depletion inhibited DPSC proliferation, accelerated senescence, and increased reactive oxygen species (ROS) levels. FTO overexpression reduced DPSC senescence, enhanced proliferation, and decreased ROS accumulation. RNA sequencing demonstrated that FTO knockdown inhibited ribosomal RNA precursor (pre-rRNA) biogenesis. We found nucleolar and coiled-body phosphoprotein 1 (NOLC1) as a novel target of FTO. NOLC1 was upregulated after FTO knockdown and promoted DPSC senescence. Mechanistically, FTO downregulation increased the m6A modifications of NOLC1 mRNA, increasing the stability of the NOLC1 mRNA. NOLC1 upregulation inhibits the transcription of pre-rRNA, causing nucleolar stress and p53 accumulation. In addition, NOLC1 knockdown partially rescued FTO deficiency-induced DPSC senescence. Our findings identified the significant role of the FTO/NOLC1/p53 axis in DPSC senescence and provide new insights to prevent the aging of DPSCs, which is beneficial for the application of DPSCs in regenerative medicine and stem cell therapy.

Figures