Abstract
IntroductionMesenchymal stem cells (MSCs)-based therapies have had positive outcomes in animal models of cardiovascular diseases. However, the number and function of MSCs decline with age, reducing their ability to contribute to endogenous injury repair. The potential of stem cells to restore damaged tissue in older individuals can be improved by specific pretreatment aimed at delaying senescence and improving their regenerative properties. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that modulates age-related signaling pathways, and hence is a good candidate for rejuvenative function.MethodsBone marrow-derived mesenchymal stem cells (BM-MSCs) were isolated from young (6-month-old) or aged (24-month-old) male donor rats. Cell proliferation was measured using the CCK8 cell proliferation assay; secretion of VEGF, bFGF, HGF, and IGF was assessed by RT-qPCR and ELISA. Apoptosis was induced by hypoxia and serum deprivation (hypoxia/SD) for up to 6 hr, and examined by flow cytometry. Expression levels of AMP-activated protein kinase (AMPK) and forkhead box class O 3a (FOXO3a) were detected by Western blotting. CD74 expression was assayed using RT-qPCR, Western blotting, and immunofluorescence.ResultsIn this study, we found that MSCs isolated from the bone marrow of aged rats displayed reduced proliferative capacity, impaired ability to mediate paracrine signaling, and lower resistance to hypoxia/serum deprivation-induced apoptosis, when compared to younger MSCs. Interestingly, pretreatment of aged MSCs with MIF enhanced their growth, paracrine function and survival. We detected enhanced secretion of VEGF, bFGF, HGF, and IGF from MIF-treated MSCs using ELISA. Finally, we show that hypoxia/serum deprivation-induced apoptosis is inhibited in aged MSCs following MIF exposure. Next, we found that the mechanism underlying the rejuvenating function of MIF involves increased CD74-dependent phosphorylation of AMPK and FOXO3a. Furthermore, this effect was abolished when CD74, AMPK, or FOXO3a expression was silenced using small-interfering RNAs(siRNA).ConclusionsMIF can rejuvenate MSCs from a state of age-induced senescence by interacting with CD74 and subsequently activating AMPK-FOXO3a signaling pathways. Pretreatment of MSCs with MIF may have important therapeutic implications in restoration or rejuvenation of endogenous bone marrow-MSCs in aged individuals.
Highlights
Mesenchymal stem cells (MSCs)-based therapies have had positive outcomes in animal models of cardiovascular diseases
We found that the mechanism underlying the rejuvenating function of migration inhibitory factor (MIF) involves increased CD74-dependent phosphorylation of AMP-activated protein kinase (AMPK) and Forkhead box class O 3a (FOXO3a)
We found that both mRNA and protein expression of cardiac MIF was markedly decreased in the older hearts (Figure 1), supporting our hypothesis that the decrease in MIF expression and activity is associated with ageing
Summary
Mesenchymal stem cells (MSCs)-based therapies have had positive outcomes in animal models of cardiovascular diseases. The potential of stem cells to restore damaged tissue in older individuals can be improved by specific pretreatment aimed at delaying senescence and improving their regenerative properties. In the last few years, many investigators have shown that transplantation of bone marrow-derived mesenchymal stem cells (MSCs) is a promising tool for the repair and regeneration of cardiomyocytes as well as restoration of heart function [2,3,4]. Clinical studies together with animal studies have shown that the regenerative potential of bone and other tissues declines progressively with age [5]. If the age-dependent decrease in regenerative potential is caused by intrinsic changes in MSCs themselves, autologous cell therapy approaches are prone to be suboptimal in older patients, who incidentally are in most need of such treatment procedures [7]. An optimum therapeutic strategy for diseases associated with old age could be identification of ways to replenish stem cell function by, for instance, rejuvenating endogenous stem/progenitor cells that might infiltrate and supply the ischemic tissue with new blood vessels to prevent tissue damage [8,9,10]
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