Autologous mesenchymal stem cell therapies involve obtaining cells from patient fat tissue or bone marrow, expanding or purifying the cells in culture, and introducing them back into the patient in order to produce benefits. The precise methodology used matters enormously, and these therapies vary widely in their effects and reliability, even between clinics that are ostensibly performing the same procedure. One issue, among many, is that cells isolated from an old patient are less effective than those from young patients. In part that is because steps taking place in culture that involve older cells will produce fewer viable cells and more senescent cells. Any approach that improves these numbers will tend to improve the therapy, whether that is achieved via culling senescent cells, partial reprogramming, or preventing cells from becoming senescent.
The beneficial functions of mesenchymal stem cells (MSCs) decline with age, limiting their therapeutic efficacy for myocardial infarction. 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 myocardial infarction. 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 myocardial infarction 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 myocardial infarction. Thus, MIF rejuvenated aged MSCs by activating autophagy and enhanced their therapeutic efficacy in myocardial infarction, suggesting a novel MSC-based therapeutic strategy for cardiovascular diseases in the aged population.