One of the areas in which stem cell therapies have shown promise right from the beginning is in the treatment of various forms of heart disease and the tissue damage caused by a heart attack, or myocardial infarction. Benefits have been evident enough for a broad clinical industry to flourish in many parts of the world well in advance of the exceedingly slow and largely unnecessary process of pushing treatments through the regulatory gauntlet in the US. A trend in the development of therapies has been from the use of transplanted stem cells obtained from donors to the use of stem cells isolated or reprogrammed from a patient's tissue samples, something that should produce a better class of result because it removes concerns regarding transplant rejection and other issues that can arise when the tissues from one person are used in another.
If using the patient's own cells in a regenerative therapy, the question of age immediately arises, however. Most people in need of regenerative treatments are in need exactly because they are old and suffering from age-related degenerative medical conditions. Their organs falter and fail, and the leading use case for present and future regenerative medicine is to at least partially compensate for or ideally turn back this downward spiral. We age because we become damaged, the machinery of cells and tissues degraded in various ways to the point of malfunction, and a part of that damage accrues to stem cell populations. Work on understanding why stem cell activity declines with aging has in recent years placed a great deal of emphasis on the state of the surrounding tissue environment rather than the cells themselves. The muscle stem cells known as satellite cells recover much of their ability to maintain tissues when moved from old tissue to young tissue, for example. This, of course, leads to more optimism for the near future of regenerative treatments for old people, provided that sizable benefits can indeed be obtained by coaxing stem cells into a more youthful and active behavior through altered levels of signal proteins such as GDF-11.
Not all types of stem cells do as well as aged satellite cells, however. Mesenchymal stem cells (MSCs), usually obtained from bone marrow or fat tissue in adults, are at present one of the most-used cell types in treatments under development as well as those available in clinics or trials. Unfortunately, there is fairly robust evidence to show that these cells don't work as well in regenerative therapies when obtained from older donors. The research group quoted below have investigated the mechanisms involved, which is the first step on the road to understanding whether or not there is a practical way to fix this problem in the near term, and thus make cells from old patients just as effective as those from young patients:
In the last decade, great successes been achieved in transplanting MSCs to treat myocardial infarction (MI) in animal models as well as in clinical trials. Previously, lower efficacy of old MSCs than the young ones in myocardial repair has been confirmed by independent studies and furthermore different potential mechanisms have been proposed, such as deteriorated paracrine capacity and impared angiogenic capacity. However, the causes why the efficacy of MSCs on myocardial repair after ischemia was attenuated with aging were far from thoroughly demonstrated. In the current study, our purpose is to determine whether other causes existed in addition to the previous findings that aging influenced the therapeutic efficacies of MSCs. We show that aging increases the susceptivity of MSCs to reactive oxygen species (ROS) and impairs their therapeutic potency for myocardial infarction. To our knowledge, this is the first evidence that MSCs from old donors were more susceptible to ROS induced adhesion impairment and apoptosis, leading to a more rapidly decreased survival rate, and thus resulting in a dampened therapeutic effectiveness.
Back to 2001, two landmark studies showed transplantation of bone marrow cells could generate de novo myocardium. Thereafter, MSCs transplantation was carried out by several clinic trials, and a promising therapeutic potential was reported. However, as autologous MSCs transplantation was favoured in clinic, and most patients were over 60 years old, one question arises - are MSCs from old donors qualified to do the job? We found an impaired therapeutic efficiency of transplantation using MSCs from old donors. Furthermore, our data suggest that this impairment may be caused directly by a significantly decreased viability of old MSCs engrafted, in which the micro-environmental ROS in the MI region may play important roles.
The co-injection of MSCs with the free radical scavenger, NAC (N-acetyl-L-cysteine) has been shown to protect MSCs from ROS and enhanced their therapeutic efficiency. In our study, in order to investigate whether MSCs from old donors were more vulnerable to the micro-environmental ROS in the MI region in vivo, besides the old and young MSCs transplantation groups, we introduced a group in which 1 mM NAC was co-injected with the old MSCs. Interestingly, we found a similar number of NAC treated old MSCs and young MSCs remained one week after transplantation, whereas the number of survived MSCs from old donors was only about a half of that of survived MSCs from young donors. In addition, judging by the histology and function of heart, we found an impaired therapeutic efficiency transplanting MSCs from old donors. Since the NAC plays its role as a ROS scavenger but does not have a significant therapeutic effect in treating MI without MSCs, we may safely indicated that MSCs from old donors has lower viability in vivo in the MI region due to their increased susceptivity to the environmental ROS.
To survive, cells require an adequate interaction between them and the extracellular matrix, otherwise they will undergo apoptosis, known as anoikis. Thus, the viability of engrafted MSCs also depends on cell adhesion. However, the infarction of myocardium created a harsh micro-environment, including an accumulation of ROS, which has been reported to hinder cell adhesion. Therefore, we postulated that the low survival rate of MSCs from old donor may be caused by an enhanced susceptibility to environmental ROS. By adhesion assay and apoptosis assay, we found that ROS caused more damage in the adhesion of old MSCs than of the young ones, which further increase the old MSCs' apoptosis indirectly.