Delivery of Mesenchymal Stem Cell Exosomes is Protective Against D-Galactose Accelerated Cardiac Aging in Mice

Delivery of Mesenchymal Stem Cell Exosomes is Protective Against D-Galactose Accelerated Cardiac Aging in Mice

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D-galactose is used in laboratory studies to accelerate aging in mice. As for any method of accelerating aging, it is really just a way of inducing cell and tissue damage in the hopes that the higher level manifestations of disease and system failure are roughly equivalent. This depends on the distribution and types of damage: natural aging is a given mix, and all of the methods of accelerating aging produce a different mix, sometimes very different. The damage induced by D-galactose isn’t as distant from normal aging as, say, DNA repair deficiencies known as progeroid syndromes: it produces a greater burden of oxidative stress, senescent cells, chronic inflammation, and metabolic dysfunction via a variety of mechanisms. These are all important in normal aging.

Here, researchers show that delivery of exosomes derived from mesenchymal stem cells is protective against the cardiac aging induced in mice by D-galactose. This effect may translate to normal aging, but that must still be tested. The most widely available of present stem cell therapies produce benefits via the signals generated by the transplanted stem cells; these cells die quite quickly rather than integrate into tissues. Given this, why not just deliver the signals? Much of cell signaling is carried via extracellular vesicles such as exosomes, and harvesting exosomes for use in therapy is a somewhat simpler prospect than the transplantation of cells. Thus this is an area of energetic exploration, and we might expect that much of the range of present day stem cell therapies will be replaced in the years ahead with some form of extracellular vesicle therapy.

Aging is a risk factor for cardiovascular disease, and oxidative stress has been considered as a possible mechanism underlying aging-related pathologies. It was hypothesized that oxidative stress is associated with inflammation, which is an important contributor of aging. However, the signaling pathway connecting oxidative stress, inflammation, and aging remains undefined, and there is no effective therapeutic approach to alleviate aging-associated cardiovascular disease. Tumor necrosis factor-α (TNF-α), one of major inflammatory cytokines, is regulated by nuclear factor kappa B (NF-κB). It was reported that ischemic injury triggers the activation of NF-κB, which activates the transcription of inflammatory cytokines such as TNF-α. However, whether NF-κB regulates TNF-α in the aging process is not known.

It is known that mesenchymal stem cells (MSC) can improve heart function after infarction, and the beneficial effect of MSCs is mediated by paracrine factors which are transported by exosomes. Exosomes contain functional miRNAs and long noncoding RNAs (lncRNA) and serve as intercellular shuttles to deliver important messages to alter the gene expression and cellular functions of distant organs. We and others have reported that bone marrow MSC-derived exosomes improve heart function after infarction, and several miRNA-mediated exosomes’ repair functions. However, it is unknown whether exosomes could prevent aging-induced cardiac dysfunction.

Because lncRNAs are more tissue-specific and developmental stage-specific compared to miRNA, we chose to investigate the role of lncRNA in exosomes. More recently, one report showed that lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with the aging process. However, it is unknown whether MSC exosomes contain lncRNA MALAT1 and whether lncRNA MALAT1 in exosomes could have a functional role in preventing aging-induced cardiac dysfunction. In this study, we explored whether umbilical mesenchymal stem cell (UMSC) derived exosomes could prevent aging-induced cardiac dysfunction and determined whether the potential mechanism was mediated by the exosome/lncRNA MALAT1/NF-κB/TNF-α pathway.

We discovered that human umbilical cord mesenchymal stem cell- (UMSC-) derived exosomes prevent aging-induced cardiac dysfunction. Silencer RNA against lncRNA MALAT1 blocked the beneficial effects of exosomes. In summary, we discovered that UMSC-derived exosomes prevent aging-induced cardiac dysfunction by releasing novel lncRNA MALAT1, which in turn inhibits the NF-κB/TNF-α signaling pathway. These findings will lead to the development of therapies that delay aging and progression of age-related diseases.


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