Autophagy inhibits the mesenchymal stem cell aging induced by D‐galactose through ROS/JNK/p38 signalling

Abstract

Autophagy and cellular senescence are two critical responses of mammalian cells to stress and may have a direct relationship given that they respond to the same set of stimuli, including oxidative stress, DNA damage, and telomere shortening. Mesenchymal stem cells (MSCs) have emerged as reliable cell sources for stem cell transplantation and are currently being tested in numerous clinical trials. However, the effects of autophagy on MSC senescence and corresponding mechanisms have not been fully evaluated. Several studies demonstrated that autophagy level increases in aging MSCs and the downregulation of autophagy can delay MSC senescence, which is inconsistent with most studies that showed autophagy could play a protective role in stem cell senescence. To further study the relationship between autophagy and MSC senescence and explore the effects and mechanisms of premodulated autophagy on MSC senescence, we induced the up-or down-regulation of autophagy by using rapamycin (Rapa) or 3-methyladenine, respectively, before MSC senescence induced by D-galactose (D-gal). Results showed that pretreatment with Rapa for 24 hours remarkably alleviated MSC aging induced by D-gal and inhibited ROS generation. p-Jun N-terminal kinases (JNK) and p-38 expression were also clearly decreased in the Rapa group. Moreover, the protective effect of Rapa on MSC senescence can be abolished by enhancing the level of ROS, and p38 inhibitor can reverse the promoting effect of H 2 O 2 on MSC senescence. In summary, the present study indicates that autophagy plays a protective role in MSC senescence induced by D-gal, and ROS/JNK/p38 signalling plays an important mediating role in autophagydelaying MSC senescence. K E Y W O R D S autophagy, mesenchymal stem cells, ROS/JNK/p38 signalling, senescence S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Zhang D, Chen Y, Xu X, et al. Autophagy inhibits the mesenchymal stem cell aging induced by D-galactose through ROS/JNK/p38 signalling. Clin Exp Pharmacol Physiol. 2020;47:466-477. https ://doi.

Curcumin induces G2/M arrest and triggers autophagy, ROS generation and cell senescence in cervical cancer cells

“…Autophagy can protect cells from dying or induce cell death, depending on the circumstances [8]. ROS and autophagy-related proteins, which regulate the autophagic response to cellular stress, counterbalance each other via multiple complex signaling pathways [9]. Under certain circumstances, ROS can also induce cellular damage and perturb specific signal transduction pathways, thereby leading to autophagic cell death, also termed Type II cell death [10].…”

Dual Role of Autophagy in Regulation of Mesenchymal Stem Cell Senescence

“…Downregulation of p-Jun N-terminal kinases (JNK) and p-38 expression could also be demonstrated in the rapamycin treated cells (Zhang et al, 2020). In addition, the protective role of rapamycin on MSC aging could be counteracted by increasing the level of ROS, and the use of p38 inhibitors could revert the senescence induction effect of H 2 O 2 on MSCs (Zhang et al, 2020). Altogether, this study indicated that autophagy exerted a protecting effect on D-gal-induced MSC senescence, and ROS/JNK/p38 cascade played a relevant mediating function in autophagy-mediated delay of MSC senescence.…”

“…These studies exemplified that the use of rapamycin for 24 h reduced MSC senescence significantly in this experimental setting, and this was accompanied by diminished ROS production. Downregulation of p-Jun N-terminal kinases (JNK) and p-38 expression could also be demonstrated in the rapamycin treated cells (Zhang et al, 2020). In addition, the protective role of rapamycin on MSC aging could be counteracted by increasing the level of ROS, and the use of p38 inhibitors could revert the senescence induction effect of H 2 O 2 on MSCs (Zhang et al, 2020).…”

“…The results of premodulated autophagy on MSC senescence were explored by up-or down-regulating autophagy through the employment of rapamycin or 3-methyladenine, respectively, prior to induction of D-galactose-mediated MSC senescence (Zhang et al, 2020). These studies exemplified that the use of rapamycin for 24 h reduced MSC senescence significantly in this experimental setting, and this was accompanied by diminished ROS production.…”

Autophagy in the Regulation of Tissue Differentiation and Homeostasis

“…Accordingly, upregulation of autophagy in hyperglycemic conditions correlates with ROS accumulation and premature senescence (Chang et al, 2015), and increased levels of autophagy-related genes have been found in senescent MSCs (Fafian-Labora et al, 2019). At variance, a protective role for rapamycin-induced autophagy accompanied by a decrease in ROS production has been shown in a Dgalactose-mediated model of MSC aging (Zhang et al, 2020), and the autophagic flux is compromised in other models of acute senescence, suggesting that functional autophagy may be required to counteract detrimental pathways whereas its negative modulation favors the establishment of cellular aging (Song et al, 2014;Capasso et al, 2015). The protective effect of autophagy may be decisive when MSCs are engrafted in regions characterized by a severe oxidative environment, such as infarcted hearts, where most of transplanted MSCs die in a few days due to hypoxic stress-induced apoptosis (Miao et al, 2017).…”