Old Stem Cells Not So Good at Repairing Heart Attack Damage

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:

Aging Increases the Susceptivity of MSCs to Reactive Oxygen Species and Impairs Their Therapeutic Potency for Myocardial Infarction

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.


"However, the underlying mechanisms of increased susceptibility of old MSCs to ROS may be rather complicated, which may include disrupted antioxidant system or anti-aging system, alterred apoptosis signaling, deteriorated function of organelles as well as attenuated adaptive capacities, ect."

How does this fit into the SENS 7 categories of damage? Is this a new 8th class of damage?

Posted by: Jim at November 14th, 2014 9:58 PM

Since 1 Oct’14, we have averaged 9 donors/day, $57/donor.
An Inexpensive & Effective SENS Fund Raising & Exposure Idea :
1) Brother P-Touch PT-2030 Label Maker ($49 @ Staples)
2) Brother TZe-S941 P-Touch Label Tape : 0.75” Black on Silver Tape ($28 @ Staples)
3) PT-2030 Settings:Length “-5” ; Font:BRU, Size:Auto, Width:2/3, Style:Normal, Line:Off, Align:Center
4) Two-Line Label : Line i) Stop Aging Now ! ; Line ii) http://www.sens.org
5) Each $28 TZe-S941 tape will make about 400 labels
6) In your city, place these at bus shelters, subway cars, buses, parking-meter ticket machines, on bikes of bike-sharing programs, etc. Get creative.

The Math :
1) 400 labels X 1 view/hour = 8000 views/day (approx.)
2) 1% of views lead to a website hit = 80 new website hits/day
3) 25% of new website hits lead to a donation = 20 donations/day
4) Implement in 10 major cities = 200 donations/day
5) At $50 per donation, that’s : $10,000/day.

It’s graffiti, yes, but it’s temporary, and it will incubate a SENS awareness campaign.
Considering the objective is to stop/reverse all human aging, it’s worth it.

Posted by: Ponce de Leon at November 14th, 2014 10:29 PM

i recently heard that some scientists were able to keep "progenitor" cells in an immortal self-renewing state, where they can just keep making more and more of them indefinitely. The type of progenitor cells were the kind that give rise to blood and vascular tissue, but they think they might be able to do it with other types.

Posted by: InternetStranger at November 15th, 2014 1:29 AM

@Jim: Consequences of the SENS damage types, most likely. The big black hole in the field is the current lack of knowledge and complexity of tracing those known root differences to their exact consequences. That's hard. Easier to fix things and see what happens rather than trace the pathways without fixing things.

Posted by: Reason at November 15th, 2014 8:54 AM

This is a simple take from a lowly college graduate... But wouldn't it make sense that increased susceptibility to ROS would follow from the simple fact of accumulated mutations?

Apoptosis to my knowledge is triggered by the failure of the cell to adhere to certain criteria, so the mechanisms of measuring that conformity and of being able to conform to those criteria might both deteriorate over time - and so would the ability of the cell to protect itself from further damages to these. The cell on the whole therefore becomes more fragile and likely to shut down in response to stressors.

Wouldn't it perhaps be necessary at some point to re-synthesize an entire individual's genome for the purpose of restoring fidelity and therefore function and hardiness to the cells we implant?

Posted by: Seth at November 15th, 2014 7:52 PM

@Seth - Or rather than random mutations (hopefully) the stem cells have been reprogrammed epigenetically to be more susceptible to ROS, perhaps as an anti cancer mechanism. That would be a lot easier to deal with than random mutation. I'm guessing the worst case scenario would be cells losing function with time internally and not being replaced by stem cell division regularly and just sitting there. That would be hard to repair perhaps.

It will be interesting to find out exactly why stem cells 'internally' age?

Posted by: Jim at November 15th, 2014 9:26 PM

One of the messages I took from this paper after a cursory read was this:

"Notably, seen from the results of both the heart histology and the heart function, the transplantation of old MSCs together with NAC had a similar therapeutic efficiency as the transplantation of young MSCs alone. Taken together, these data suggest an impaired potential of aged MSCs in repairing infarcted myocardium, which is caused largely by the ROS in MI micro-environment."

I am not rat cardiologist, so I am unsure what are normal parameter values in the rat for the functional assessments they performed. Using N-acetyl-L-cysteine (NAC) with the old MSCs seems to solve the susceptibility to in vivo ROS-related cell death. A couple of experiments they could have additionally performed include utilizing PBS + NAC and young MSCs + NAC for comparison. The former to assess ROS scavenger effects on (non-cell intervention) healing and the latter to assess whether or not NAC could enhance young MSC restoration of function.

They looked at the hearts 4 weeks post-treatment. Long term functional assessment and survival curves (relative to PBS controls) might provide additional insight. For example, it may be that long term maintenance of the restorative effects may be worse in the mice receiving older MSCs + NAC relative to the mice receiving younger MSCs. Though the infarct model they may use may not be conducive to this approach.

Posted by: aaron at November 17th, 2014 12:45 AM

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