Superoxide dismutase 3 protects mesenchymal stem cells through enhanced autophagy and regulation of FoxO3a trafficking

Abstract

Therapeutic applications of mesenchymal stem cells (MSCs) are limited due to their early death within the first few days of transplantation. Therefore, to improve the efficacy of cell-based therapies, it is necessary to manipulate MSCs so that they can resist various stresses imposed by the microenvironment. Moreover, the role of superoxide dismutase 3 (SOD3) in regulating such survival under different stress conditions remain elusive. In this study, we overexpressed SOD3 in MSCs (SOD3-MSCs) and evaluated its effect under serum starvation conditions. Nutritional limitation can decrease the survival rate of transplanted MSCs and thus can reduce their efficacy during therapy. Interestingly, we found that SOD3-MSCs exhibited reduced reactive oxygen species levels and greater survival rates than normal MSCs under serum-deprived conditions. In addition, overexpression of SOD3 attenuated starvation-induced apoptosis with increased autophagy in MSCs. Moreover, we have demonstrated that SOD3 protects MSCs against the negative effects of serum deprivation via modulation of AMP-activated protein kinase/sirtulin 1, extracellular signal-regulated kinase activation, and promoted Forkhead box O3a trafficking to the nucleus. Taken together, these results demonstrate that SOD3 promotes MSCs survival and add further evidence to the concept that SOD3-MSCs may be a potential therapeutic agent with better outcomes than normal MSCs for various diseases involving oxidative stress and compromised MSCs survival during therapy.

Insights into superoxide dismutase 3 in regulating biological and functional properties of mesenchymal stem cells

“…Recently, it was observed that overexpression of SOD3 enhances the survival rate of UCB-MSCs under nutrientdeprived condition. Similarly, SOD3 attenuated starvation-induced apoptosis with reduced ROS levels under serum-starved condition [37]. Autophagy found to protect MSCs from oxidative stress-induced cell death.…”

“…However, SOD3 does not affect the expression levels of prostaglandin E2 and galectin-1 which are well known immunomodulatory regulators in MSCs [21]. Moreover, Overexpression of SOD3 was not found to regulate the cell size, complexity, and stemness of UCB-MSCs [37].…”

“…Similarly, depletion of autophagic proteins such as Microtubule-associated proteins 1A/1B light chain 3B (LC3B) and beclin-1 in MSCs found to exaggerate oxidative stress-induced injury with decreased intracellular ATP and increased ROS [39]. Endogenous SOD3 level was found to regulate autophagic induction under normal and nutrientdeprived conditions as the expression of both SOD3 and LC3-II found to increase from 3 h and declined subsequently after 48 h [37]. Overexpression of SOD3 enhances autophagy in MSCs during serum-starved condition through increased AMPK/sirtulin-1 activation, promotion of Forkhead box O3a into the nucleus and activation of extracellular signal-regulated kinase pathway [37].…”

“…The overexpression of SOD3 in MSCs found to increase its immunosuppressive properties through enhanced secretion of IL-1Ra, TGF-β, IL-10, HO-1, and IDO-1 which are well-known immunosuppressive agents with increased inhibition of T cell differentiation during inflammation [21]. Similarly, SOD3 over-expressed MSCs found to enhance autophagy and prolong survival rate of starved MSCs through modulation of autophagic regulatory signals such as SIRT1/ AMPK/AKT/FoxO3a/ERK, and reduced starvationinduced oxidative stress and apoptosis [37]. SOD3 also found to suppress TLR-7-induced downstream NF-κB, and JAK-STAT signaling pathway in imiquimod-induced psoriasis-like skin inflammation mouse model [21].…”

“…Endogenous SOD3 level was found to regulate autophagic induction under normal and nutrientdeprived conditions as the expression of both SOD3 and LC3-II found to increase from 3 h and declined subsequently after 48 h [37]. Overexpression of SOD3 enhances autophagy in MSCs during serum-starved condition through increased AMPK/sirtulin-1 activation, promotion of Forkhead box O3a into the nucleus and activation of extracellular signal-regulated kinase pathway [37].…”