Sirtuin3 protects aged human mesenchymal stem cells against oxidative stress and enhances efficacy of cell therapy for ischaemic heart diseases

Abstract

Sirtuin3 (SIRT3) is associated with oxidative stress and lifespan. However, the possible mechanisms underlying its influence are unknown. We hypothesized that SIRT3 increases the antioxidant capacity of aged cells and improves the efficacy of human mesenchymal stem cell (hMSC) therapy for ischaemic heart diseases in aged patients. In vitro, the antioxidant capacity of old hMSCs (O‐hMSCs) was increased after SIRT3 overexpression using a gene transfection technique, while the antioxidant capacity of young hMSCs (Y‐hMSCs) was decreased by SIRT3 silencing. The levels of forkhead box O3a (FoxO3a) in the nucleus, and antioxidant enzymes Mn‐superoxide dismutase (MnSOD) and catalase (CAT) increased in SIRT3‐overexpressed O‐hMSCs while they decreased in SIRT3‐silenced Y‐hMSCs after oxidative stress. Following myocardial infarction in adult rats in vivo, infarct size decreased and cardiac function was significantly enhanced after cell transplantation with SIRT3 overexpressed O‐hMSCs. The number of apoptotic cells decreased and the survival rate of transplanted cells increased following SIRT3 overexpression in O‐hMSCs. SIRT3 protects aged hMSCs against oxidative stress by positively regulating antioxidant enzymes (MnSOD and CAT) via increasing the expression of FoxO3a in the nucleus. The efficacy of aged hMSC transplantation therapy for ischaemic heart diseases can be improved by SIRT3 overexpression.

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

“…Likewise, the overexpression of SIRT3 improves the antioxidant capacity and promotes the survival of old human MSCs through activating forkhead box O3a in the nucleus, manganese-superoxide dismutase, and catalase. In an MI model, the application of old human MSCs overexpressing SIRT3 enhanced cardiac function and decreased infarct size[ 105 ]. SIRT6 maintains hMSC homeostasis by co-activating the antioxidant nuclear factor erythroid 2-related factor 2 pathway, RNA polymerase II, and heme oxygenase 1[ 106 ].…”

Withaferin A Exerts Preventive Effect on Liver Fibrosis through Oxidative Stress Inhibition in a Sirtuin 3-Dependent Manner

“…Zhang et al found that SIRT3 could protect aged human mesenchymal stem cells (hMSCs) against oxidative stress by positively regulating antioxidant enzymes Mn-SOD and CAT. SIRT3 overexpression increased the antioxidant capacity of hMSCs, while SIRT3 silence decreased the antioxidant capacity [ 56 ]. In the present study, SIRT3 depletion or SIRT3 KO clearly attenuated the promoting effect of WFA on the activities of CAT, GR, GPx, HO-1, and SOD both in activated HSCs and in fibrotic livers, which further suggested that SIRT3 mediates the oxidative stress mainly through the regulation of the activities of a mitochondrial antioxidant enzyme.…”

C1q/tumor necrosis factor-related protein-3-engineered mesenchymal stromal cells attenuate cardiac impairment in mice with myocardial infarction

“…Oxidative stress has been also reported to lead to loss of transplanted MSCs 4 . Increased antioxidant capacity protect transplanted MSCs from the harsh microenvironment and improves MSCs efficacy for ischemic heart diseases 11,27 . Therefore, it is of great need to identify approaches to promote MSCs engraftment and survival.…”