Abstract
The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged MSCs and increase their therapeutic efficacy in MI. Young and aged MSCs were isolated from the bone marrow of young and aged donors. Young MSCs, aged MSCs, and MIF-overexpressing aged MSCs were transplanted into the peri-infarct region in a rat MI model. Aged MSCs exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young MSCs. Knocking down MIF in young MSCs induced cellular senescence, whereas overexpressing MIF in aged MSCs reduced cellular senescence. MIF rejuvenated aged MSCs by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine. MIF-overexpressing aged MSCs induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged MSCs, and had improved heart function and cell survival more effectively than aged MSCs four weeks after MI. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in MI, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.
Highlights
Despite advances in pharmacological therapy and surgical intervention, myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide
Overexpression of migration inhibitory factor (MIF) in aged mesenchymal stem cells (MSCs) increased their growth rate and delayed the arrest of their growth until passage 10 (Figure 2F). These findings suggest that MIF inhibits the cellular senescence of MSCs, and that overexpression of MIF can attenuate the senescence of aged MSCs
MIF expression was inversely associated with MSC senescence, so the downregulation of MIF in young MSCs led to cellular senescence
Summary
Despite advances in pharmacological therapy and surgical intervention, myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Mesenchymal stem cell (MSC)-based therapy is a novel treatment strategy for MI, and MSCs have the unique advantages of easy isolation, low immunogenicity and multiple lineage potential [1,2,3]. The therapeutic activity of MSCs in MI has been predominantly attributed to their paracrine effects, rather than their differentiation [2, 4]. Autologous MSCs isolated from aged individuals have dramatically lower functional capacities (e.g., ability to survive in the ischemic heart and exert paracrine effects) than those from young individuals, and have limited therapeutic efficacy for MI [1, 5,6,7]. It is greatly important to explore novel strategies of rejuvenating autologous aged MSCs to enhance their benefits for MI treatment. Recent studies have revealed that genetic modification is an effective way to rejuvenate aged MSCs [8, 9]
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