Cell-penetrating superoxide dismutase attenuates oxidative stress-induced senescence by regulating the p53-p21Cip1 pathway and restores osteoblastic differentiation in human dental pulp stem cells

Abstract

Background Human dental pulp stem cells (DPSCs) have potential applications in tissue regeneration because of their convenient cell harvesting procedures and multipotent capacity. However, the tissue regenerative potential of DPSCs is known to be negatively regulated by aging in long-term culture and under oxidative stress. With an aim of reducing cellular senescence and oxidative stress in DPSCs, an intracellular delivery system for superoxide dismutase 1 (SOD1) was developed. We conjugated SOD1 with a cell-penetrating peptide known as low-molecular weight protamine (LMWP), and investigated the effect of LMWP-SOD1 conjugates on hydrogen peroxide-induced cellular senescence and osteoblastic differentiation. Results LMWP-SOD1 significantly attenuated enlarged and flattened cell morphology and increased senescence-associated β-galactosidase activity. Under the same conditions, LMWP-SOD1 abolished activation of the cell cycle regulator proteins, p53 and p21 Cip1 , induced by hydrogen peroxide. In addition, LMWP-SOD1 reversed the inhibition of osteoblastic differentiation and downregulation of osteogenic gene markers induced by hydrogen peroxide. However, LMWP-SOD1 could not reverse the decrease in odontogenesis caused by hydrogen peroxide. Conclusion Overall, cell-penetrating LMWP-SOD1 conjugates are effective for attenuation of cellular senescence and reversal of osteoblastic differentiation of DPSCs caused by oxidative stress inhibition. This result suggests potential application in the field of antiaging and tissue engineering to overcome the limitations of senescent stem cells.

Doxorubicin-Mediated Bone Loss in Breast Cancer Bone Metastases Is Driven by an Interplay between Oxidative Stress and Induction of TGFβ

“…Smietana et al have reported that loss of SOD1 resulted in weaker bone and lower bone mineral density in mice [64]. SOD1 has been reported to restore osteoblast differentiation by attenuating oxidative stress in human dental pulp cells [65], which is in agreement with our result that treatment with antioxidant agent NAC was able to rescue doxorubicin-mediated decrease in osteoblast differentiation. An inverse relationship was noted between TGFβ1 and SOD1 activity in radiation-mediated fibrosis models [66], [67].…”

Peer Review #2 of "Sclerostin promotes human dental pulp cells senescence (v0.1)"

“…These data are in accordance with previous findings that p16, p53 and p21 are highly expressed in senescent dental pulp cells (Mas-Bargues et al, 2017;Muthna et al, 2010). Conversely, downregulation of p53-p21 decreased senescence of dental pulp stem cells (Choi et al, 2012). Meanwhile, p16 knockdown significantly reduced senescence-related dysfunction of dental pulp mesenchymal stem cells (Feng et al, 2014).…”

Ionic silicon improves endothelial cells' survival under toxic oxidative stress by overexpressing angiogenic markers and antioxidant enzymes

“…However, SOD-1, Cat-1, and NOS3 were considered in our study, due to their close correlation with angiogenesis and osteogenesis (Choi et al, 2012;Fernández et al, 2009;Gabryel et al, 2016;Ilyas et al, 2016). Moreover, the SOD-1 demonstrated a protective effect in HUVECs under oxidative stress and oxygen deprivation, reducing apoptosis of endothelial cells (Gabryel et al, 2016).…”

“…We also investigated the effect of ionic silicon on gene expression of antioxidant, superoxide dismutase-1 (SOD-1), catalase-1 (Cat-1), and nitric oxide synthase-3 (NOS3) produced by endothelial cells. These oxidative stress markers play a relevant role in the reduction of deleterious oxidative stress and facilitation of angiogenesis and osteogenesis during the tissue-healing process (Choi, Lee, Chung, & Park, 2012;Diwan, Wang, Jang, Zhu, & Murrell, 2000;Fernández, San Miguel, & Fernández-Briera, 2009;Matsunaga et al, 2002;Murohara et al, 1998).…”