Aging Increases the Susceptivity of MSCs to Reactive Oxygen Species and Impairs Their Therapeutic Potency for Myocardial Infarction

Abstract

Myocardial infarction (MI) is one of the leading causes of death worldwide and Mesenchymal Stem Cells (MSCs) transplantation has been considered a promising therapy. Recently, it was reported that the therapeutic effectiveness of MSCs is dependent on the age of the donor, yet the underlying mechanism has not been thoroughly investigated. This study was designed to investigate whether this impaired therapeutic potency is caused by an increased susceptivity of MSCs from old donors to reactive oxygen species (ROS). The MSCs were isolated from the subcutaneous inguinal region of young (8–10 weeks) and old (18 months) Sprague–Dawley (SD) rats. By exposing these MSCs to H2O2, we found that the adhesion of MSCs from old donors was damaged more severely. Specifically, decreased expression of integrin and reduced phosphorylation of focal adhesion kinase Src and FAK were observed. Furthemore, H2O2 triggered an increased apoptosis of MSCs from old donors. To study the viability and therapeutic potency of MSCs from young and old donors in vivo, these MSCs were transplanted into acute MI model rats. We observed a more rapidly decreased survival rate of the old MSCs in the infarct region, which may be caused by their increased susceptivity to the micro-environmental ROS, as transplantation of the old MSCs with N-acetyl-L-cysteine (NAC), a ROS scavenger, protected them. The low viability of engrafted old MSCs consequently impaired their therapeutic effectiveness, judging by the histology and function of heart. Our study may help to understand the mechanism of MSCs-host interaction during MI, as well as shed light on the design of therapeutic strategy in clinic.

Klotho gene‐modified BMSCs showed elevated antifibrotic effects by inhibiting the Wnt/β‐catenin pathway in kidneys after acute injury

“…Our study demonstrated that transplantation of Klotho-GFP-BMSCs into IRI mice ameliorated the loss of renal function and renal interstitial fibrosis, and the renal protective effect of Klotho-modified BMSCs was more powerful than that of normal BMSCs. In both in vivo and in vitro experiments, BMSCs showed a tendency toward aging that led to a decline in proliferative ability and function (Krinner et al, 2010;Li et al, 2014). Aging also limited the therapeutic effects of BMSCs.…”

Curcumin Affects Adipose Tissue-Derived Mesenchymal Stem Cell Aging Through TERT Gene Expression

“…Other factors involved in the aging process are oxidative stress-mediated cellular damage via reactive oxygen species (ROS) [34]. Recently, Liang et al reported that aging increases the susceptibility of MSCs to ROS and impairs their therapeutic potency [35]. Britt-Compton et al indicated that more intense ROS-generating stressors can induce senescence through the generation of telomere-independent DNA damage [36].…”

Regulation of the mitochondrial reactive oxygen species: Strategies to control mesenchymal stem cell fates ex vivo and in vivo

“…one of these studies analysed 53 human donors ranging within 13-80 years demonstrated no significant correlation between age and T cell suppression capability. 67 Moreover, although Li et al 69 tivating pRb signalling. 22 Overall, MSC senescence is closely linked to ROS-related pathways and senescence-related gene expression, which lead to apoptosis and necrosis in MSCs.…”

“…Another studies conflict with the assertion that donor age negatively impacts MSC suppression of T cell proliferation; one of these studies analysed 53 human donors ranging within 13‐80 years demonstrated no significant correlation between age and T cell suppression capability . Moreover, although Li et al demonstrated that MSCs derived from old donors showed a more rapidly decreased survival rate than MSCs derived from young donors in the infarct region in acute myocardial infarction (MI) model, N‐acetyl‐L‐cysteine (NAC) which is a ROS scavenger can protected MSCs derived from old donors from apoptosis in vivo and significantly enhanced the therapeutic effects of MSCs. Long‐term culture always results in proliferative decline, cell cycle arrest and decreased differentiation capacity in adipose‐derived MSCs by ROS‐induced suppression of c‐Maf .…”