Insulin-like growth factor binding proteins 7 prevents dental pulp-derived mesenchymal stem cell senescence via metabolic downregulation of p21.

Abstract

Cellular senescence affects the efficacy of mesenchymal stem cells (MSCs)-mediated tissue regeneration. Insulin-like growth factor binding proteins-7 (IGFBP7), as a member of the IGF family, is associated with osteogenic differentiation and the senescence of MSCs, but its exact function and mechanism remain unclear. We found IGFBP7 promoted the osteogenic differentiation and prevented the senescence of dental pulp-derived MSCs (DPSCs), as observed in the gain-of-function and loss-of-function analyses, the senescence-associated marker p21 showed the most pronounced expression changes. We demonstrated that IGFBP7 activated the biological activity of SIRT1 deacetylase via metabolism, resulting in a deacetylation of H3K36ac and a decrease of the binding affinity of H3K36ac to p21 promoter, thereby reducing the transcription of p21, which ultimately prevents DPSCs senescence and promotes tissue regeneration. The activation of the mitochondrial electron transport chain (ETC) by Coenzyme Q10 could rescue the promotion of DPSC senescence induced by the knockdown of IGFBP7, whereas the inhibition of ETC by rotenone attenuated the prevention of DPSC senescence induced by IGFBP7 overexpression. In conclusion, our present results reveal a novel function of IGFBP7 in preventing DPSC senescence via the metabolism-induced deacetylation of H3K36ac and reduction of p21 transcription, suggesting that IGFBP7 is a potential target for promoting tissue regeneration in an aging environment.