Reviewing the Literature on Prevention of Cellular Senescence in Stem Cells

In today's open access paper, the authors report on a literature search for efforts to reduce cellular senescence in stem cell populations. The majority of the work they list, involving the assessment of pharmacological agents that can influence the onset of cellular senescence, has taken place in cell cultures, an environment that has very little relevance to what happens in stem cell niches in a living organism. Stem cells in a petri dish undergo very different rates of replication, have different stresses and signals, are not subject to interactions with supporting cells of the niche, and so forth.

Thus I'd be inclined to give little attention to the in vitro work, at least in the context of developing drugs to be used to reduce cellular senescence in vivo by altering cellular metabolism in ways that lower the rate at which cells become senescent. The environments are so very different, a petri dish versus living tissue. This in vitro work is of interest in the context of manufacturing stem cell therapies, however.

Recent evidence suggests that the degree to which stem cells become senescent when expanded in culture influences whether or not the therapeutic use of those cells produces benefits. Since small differences in manufacture can lead to sizable differences in the proportion of cells that become senescent, this could explain the wide variability of efficacy from clinic to clinic and patent to patient that is observed in the use of first generation stem cell therapies. Senescent cell accumulation is an important contributing cause of aging, and if even a modest percentage of injected cells are senescent, that may be enough to offset the benefits of such a therapy. Stem cells produce benefits via their signaling, and senescent cells cause harm via their signaling.

In search of elixir: Pharmacological agents against stem cell senescence

Stem cell senescence has been studied in aging, diseases, adverse drug effects, and as a challenging phenomenon in cell therapy. The most investigated types of these cells are endothelial progenitor cells (EPCs), hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs). Other investigated kinds include cardiac progenitor cells (CPCs), myeloblasts, and induced pluripotent stem cells (iPSCs). EPCs are involved in vascular homeostasis and new blood vessel regeneration. The decrease in their functional cell number is associated with aging and atherosclerotic processes. HSCs are involved in blood coagulation, oxygen transportation, and immune system function, so their senescence leads to blood dysfunction. MSCs exist in many tissues, including bone marrow, adipose tissue, the bloodstream, and cord blood. MSCs have high self-renewal capacity and the ability to differentiate into other kinds of cells, such as adipocytes, chondrocytes, and osteoblasts, depending on their host organ. Although adult stem cells appear to be valuable sources for regeneration, they have limited sources, differentiation, and expansion potential. However, differentiated cells can be reprogrammed to iPSCs and then differentiated to desired cell types.

This manuscript examines protective medicines and supplements which are capable of hindering stem cell senescence. As reviewed in this paper, most of these protective agents increased telomerase activity or decreased oxidative damage via various anti-oxidant mechanisms, which ultimately inhibited cellular senescence. Senescence prevention in the body results in health and longevity. Various medicines inhibit senescence through different mechanisms. As mentioned in this review, 17β-estradiol, melatonin, metformin, rapamycin, coenzyme Q10, N-acetyl cysteine, and vitamin C were the most studied agents in different kinds of stem cells. Although most of these studies were in vitro, we can consider these agents in cell therapy to increase the shelf life and the functional cell number of donated stem cells before transplantation to achieve more clinical success. Moreover, in vitro studies are the first step towards clinical studies. Although more studies are necessary for clinical application, these reviewed agents have been used in the clinical setting for different purposes for a long time; therefore, we only need to evaluate their systemic anti-senescence effects and effective anti-senescence dosages.

We conclude that off-label use of approved medicines and supplements is a convenient, safe, and economical approach to prevent stem cell senescence both in vitro and in vivo. These agents provide a wide range of options based on targeted cells. Since all of them have passed substantial safety trials, we only need to determine their effective dosage to prevent stem cell senescence. Maybe it seems that heterogeneity of administration, patients, and diseases can make repurposing inefficient and time-consuming. Still, in comparison with discovering new anti-senescence agents, this approach is much more economical and accessible. Moreover, performing retrospective studies for each medicine can address these issues.

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