In the past, I’ve written that there is a strong suggestion that MSCs from older individuals are less likely than those from young ones to fight diseases, but that the evidence—though strong—is mainly circumstantial. However, two very recent studies have shown direct and convincing evidence that this is indeed the case. In one study, from Dr. Matsuo’s laboratory at Nagasaki University, the authors show that rats that are treated with MSCs from a young adult human after stroke do much better than control (a well known and often repeated finding), but that this effect is completely abolished if the MSCs are harvested from an older individual. In the other study, from Dr. Chen’s group at the National Clinical Research Center for Kidney Diseases in Beijing, the authors found that the composition of the biomolecules that are secreted by MSCs (most researchers in the field, me included, ascribe to the hypothesis that the molecules that MSCs secrete are what give them their regenerative powers) change in aged rats, and that this change can lead to kidney degeneration as the rat ages. Let’s look at both studies in greater detail below.
Study: Recovery Treatment from Stroke in a Rat
In the first study, which to my knowledge isn’t published yet, but was presented at the International Stroke Conferencethis past February (and which I had the good fortune to witness), the researchers compared the effects of cells from two human donors on recovery from stroke in a rat. The use of MSCs for treatment of stroke was pioneered by my mentor, and has been repeated by many groups around the globe. The effect is well studied enough that there is a large-scale human trial now underway being led by Dr. Gary Steinberg at Stanford University (stay tuned for a blog on that topic when the results are released!). So, unsurprisingly, the researchers at Nagasaki University found that their MSC treated rats recovered nicely compared to non-treated control rats in their stroke model (the main test they used is called a “neurologic severity score,” which employs a battery of motor tasks to assess how easily the rat can move around its environment). In that group, they used MSCs harvested from a single 24 year old male donor. They then treated a group of rats with MSCs that had been harvested from a 64 year old donor. Interestingly, these rats performed no better than control in their recovery.
The group looked at the brains of the rats and found something rather remarkable. The brains of rats that had been treated with young donor MSCs had a different geometry from those of control or old donor recipients. The brain is made up of many cells and cell types, but the majority is a cell called an astrocyte. Astrocytes do many things, including providing nutrients to neurons and assisting in inflammatory responses, but their longest studied and most well understood function is to give the brain structure. Some of that structure is lost when one suffers an injury and tissue dies. One of the challenges of recovery is for the body to regrow cells while maintaining the order in the damaged organ. Disordered tissue often will not function properly, because barriers are erected and communication is disrupted. The authors of this study found that in the brains of rats that were treated with young, viable cells, the astrocytes were able to reorder themselves to allow for optimal growth (it is considered necessary by most researchers that new neuronal growth takes place for recovery to occur, since neurons are required for central nervous system control of movement, thought, speech, etc.), and they formed a beautiful radial pattern in the damaged region. However, in the old donor animals, disorder reigned, as it did in untreated animals. The authors argue that this is an important observation, because when the astrocytes are lined up incoherently, they present a physical barrier to other cells that need to grow, migrate, and connect with one another.
The authors did not speculate on the reason that old cells weren’t functional. For that, we turn to the next study that I mentioned above. In this study, the authors were interested in renal fibrosis, a condition in which the kidneys harden, leading to kidney failure. It has been shown in many previous studies that functional MSCs can inhibit kidneys from becoming fibrotic, and thereby help to maintain overall kidney health. As we age, our kidneys (and other cell types) are susceptible to a condition known as “epithelial-mesenchymal transition,” or EMT, where cells begin to behave in ways that can lead to fibrosis, cancer, or other pathological conditions. The authors used bone marrow MSCs to investigate whether they could affect EMT in cultured kidney cells. They harvested MSCs from 3 months and 24 months old rats (roughly equivalent to, say, a 20 year and 60 year old human). They then harvested the microvesicles (tiny bubbles full of protein and nucleic acid) from the MSCs and treated kidney cells with them. They found that cells that were treated with young microvesicles were much less likely to undergo EMT than cells treated with old microvesicles when the cells were stimulated with a protein that is known to induce EMT. They then searched for the underlying molecular biology of this phenomenon, and they found that several specific RNA species were lacking in the old microvesicles compared to the young ones. When they supplemented the kidney cells with just a couple of these RNAs, they were able to protect them from undergoing EMT, similar to when the kidney cells were treated with young microvesicles. Altogether, their data suggest that as we age our MSCs are either unable to produce the proper molecules or that they can’t secrete them efficiently, and that this contributes to age associated diseases.
Neither of these studies is perfect. For example, in the stroke study, only one MSC donor from each age group was tested. To generalize their claim, the authors certainly will need to show that this phenomenon happens across many donors and both genders. It would also be instructive if they or others investigated the effect of donor age on other diseases that MSCs have been shown to treat—recovery from heart attack, for example. The data are incomplete, but very intriguing and informative nonetheless. In the second study, it will be necessary for the researchers to treat rats with kidney fibrosis with microvesicles from the MSCs of old and young rats. The major shortcoming of their study is that the data were mainly derived from culture studies, which can give many clues as to what is happening biologically, but are not a surrogate for whole animal disease models, where circumstances are far more complex.
Still, despite these limitations (and of course every study has limitations), both of these groups have given us compelling data about what happens to our MSCs as we age, and how these changes might adversely affect our health. It is heartening to see more attention paid to this critical issue, and offers even deeper rationale for why we here at Forever Labs believe it is so critical to protect this vital resource while it’s still available. I am definitely looking forward to what these two forward thinking groups publish in the future