An interesting study came to my attention recently. Last year, a group out of Hannover Medical School in Germany published a report entitled, “ Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system. ” That’s a bit of jargon, and if you click through, you’ll find even more. So I’ll try to break it down for you to make it digestible (after all, that’s my job, no?).

In biology, we don’t usually have sick animals at our disposal, so we use “models” of disease that attempt to replicate underlying causes, or at the very least symptoms, of a disease, so that we can study how to treat them. In this paper, the authors studied two different models of multiple sclerosis (MS). MS degrades a substance in the brain called myelin. If we think of brain cells like wires that conduct electrical signals, then we can think of myelin as the insulation on the wires. In MS, myelin is degraded, and immune cells come in and “eat” the myelin. One of the troubles with MS from a scientific perspective is that no one really knows what causes it. There are two competing theories, broadly speaking. One is that the immune cells are inappropriately attacking the myelin, and the other is that the myelinating cells start to die, and the immune cells come in after to clean up. More simply, do the immune cells cause the disease or are they secondary?

The competing camps have developed two models of MS to test how we can treat each disease state. The immune camp has developed a model called “experimental autoimmune encephalitis,” or EAE for short. In EAE, the animal is stimulated in such a way that immune cells from the blood invade the brain and cause havoc. The degenerative camp favors the other model, called “cuprizone,” from its namesake, which is a poison that destroys myelin.

In the aforementioned study, the authors compared the use of bone marrow MSCs to treat both models. What they found was quite interesting. MSCs alleviated symptoms, and helped regrow the injured brain in the EAE model, but not in the cuprizone model. The authors conclude that in the absence of peripheral immune system infiltration that MSCs are not functional. That is, perhaps one of MSCs’ main modes of action is in attenuating the inflammatory response, and not through directly promoting regeneration. This is a phenomenally exciting possibility and also, I have to say, fairly controversial.

Why is it controversial? Lots of time, money, and reputations have been staked on the use of MSCs for regeneration. There are countless cell culture studies where MSCs or their products are used to treat cells, and then the authors report observing a measurable effect on growth. We’ve seen studies of this sort in brain cells, heart cells, you name it. But what if all these studies are artifacts of cell culture, and not at all what happens in the whole organism? Does it matter? I would argue it does. We don’t really know how MSCs work in disease treatment. It isn’t exactly necessary to understand mechanism of action to apply treatment. I always like to remind people that the internal combustion engine was invented before the ideal gas law (the principle that governs how gas expands when heated) was discovered. That never stopped an engine from running—but it definitely stopped them from running efficiently. We can do a lot without fully understanding how a given system works, but we can do so much more when we do understand.

The anti-inflammatory effects of MSCs are well studied, but how much is MSC treatment dependent on the immune system to function at all? A recent review by the visionary physician Sean Savitz asked this very question (well worth reading if you have the patience to get through a scientific paper). In that paper, Dr. Savitz specifically looked at all the literature regarding cell-based therapies for stroke. Stroke is of course a very separate disease from MS, but they certainly have some common features with respect to regeneration of the brain, so there is merit in comparing them. One of the main arguments for the anti-inflammatory hypothesis is that MSCs have a profoundly positive effect on recovery when injected in to the bloodstream. However, many of the cells that are injected this way get stuck in peripheral organs. Two of the main organs that the cells end up in are the lungs and the spleen, both of which have large resident populations of immune cells. Scientists have observed that when the MSCs stick to each organ, that they stimulate the resident immune cells to release anti-inflammatory signals that calm the body’s systemic inflammatory response. There is strong evidence that several types of stem cells beyond MSCs act directly on the spleen when delivered after stroke, and that the spleen in turn releases anti-inflammatory molecules. Many studies have demonstrated that these anti-inflammatory factors both protect from injury and promote regeneration.

On the other hand, what about when cells are injected straight into the brain, as in the recent stroke trial that I wrote about ? It has been shown in both stroke and traumatic brain injury that one of the immediate effects of injecting cells directly into the brain is to modulate the phenotype of the resident brain immune cells (called microglia). When immune cells become active, they can act either pro- or anti-inflammatory. Stroke and other neural injuries activate the microglia into their pro-inflammatory phenotype. Injecting MSCS into the brain appears to have the effect of reprogramming the microglia from being pro-inflammatory to anti-inflammatory. This reprogramming then might clear the way for brain cells to grow and thrive, which is ultimately necessary for a sufferer of a brain injury to regain function.

This work is fascinating, but with MSCs, the story is not usually so simple. I think that it is likely that MSCs act more efficiently on the brain with an intact and functional immune system, but it is doubtful that it is the sole mechanism. Too much literature exists that shows MSCs can secrete factors that have an immediate impact on the microenvironment. One thing this works does highlight, however, is that we're all integrated wholes, and that we need each of our systems to functional properly to be healthy.
​
How might all this affect you? Hopefully, none of you will have a stroke, brain injury, MS, or any other debilitating disease to deal with. But even in the absence of a specific disease, the inflammatory hypothesis could prove to be important for Forever Labs customers. As we age, many of us become chronically inflamed. Chronic inflammation correlates to everything from arthritis to Alzheimer’s to cancer. We here at Forever Labs like to envision a world in which we can use our cells to reduce systemic inflammation periodically. It remains to be seen what the optimal conditions from this type of prophylactic treatment might be, but the more data that are out there, the more it seems likely the future of medicine is in controlling the immune system. Beyond doubt, MSCs will be a big part of that equation.

An interesting study came to my attention recently. Last year, a group out of Hannover Medical School in Germany published a report entitled, “ Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system. ” That’s a bit of jargon, and if you click through, you’ll find even more. So I’ll try to break it down for you to make it digestible (after all, that’s my job, no?).

In biology, we don’t usually have sick animals at our disposal, so we use “models” of disease that attempt to replicate underlying causes, or at the very least symptoms, of a disease, so that we can study how to treat them. In this paper, the authors studied two different models of multiple sclerosis (MS). MS degrades a substance in the brain called myelin. If we think of brain cells like wires that conduct electrical signals, then we can think of myelin as the insulation on the wires. In MS, myelin is degraded, and immune cells come in and “eat” the myelin. One of the troubles with MS from a scientific perspective is that no one really knows what causes it. There are two competing theories, broadly speaking. One is that the immune cells are inappropriately attacking the myelin, and the other is that the myelinating cells start to die, and the immune cells come in after to clean up. More simply, do the immune cells cause the disease or are they secondary?

The competing camps have developed two models of MS to test how we can treat each disease state. The immune camp has developed a model called “experimental autoimmune encephalitis,” or EAE for short. In EAE, the animal is stimulated in such a way that immune cells from the blood invade the brain and cause havoc. The degenerative camp favors the other model, called “cuprizone,” from its namesake, which is a poison that destroys myelin.

In the aforementioned study, the authors compared the use of bone marrow MSCs to treat both models. What they found was quite interesting. MSCs alleviated symptoms, and helped regrow the injured brain in the EAE model, but not in the cuprizone model. The authors conclude that in the absence of peripheral immune system infiltration that MSCs are not functional. That is, perhaps one of MSCs’ main modes of action is in attenuating the inflammatory response, and not through directly promoting regeneration. This is a phenomenally exciting possibility and also, I have to say, fairly controversial.

Why is it controversial? Lots of time, money, and reputations have been staked on the use of MSCs for regeneration. There are countless cell culture studies where MSCs or their products are used to treat cells, and then the authors report observing a measurable effect on growth. We’ve seen studies of this sort in brain cells, heart cells, you name it. But what if all these studies are artifacts of cell culture, and not at all what happens in the whole organism? Does it matter? I would argue it does. We don’t really know how MSCs work in disease treatment. It isn’t exactly necessary to understand mechanism of action to apply treatment. I always like to remind people that the internal combustion engine was invented before the ideal gas law (the principle that governs how gas expands when heated) was discovered. That never stopped an engine from running—but it definitely stopped them from running efficiently. We can do a lot without fully understanding how a given system works, but we can do so much more when we do understand.

The anti-inflammatory effects of MSCs are well studied, but how much is MSC treatment dependent on the immune system to function at all? A recent review by the visionary physician Sean Savitz asked this very question (well worth reading if you have the patience to get through a scientific paper). In that paper, Dr. Savitz specifically looked at all the literature regarding cell-based therapies for stroke. Stroke is of course a very separate disease from MS, but they certainly have some common features with respect to regeneration of the brain, so there is merit in comparing them. One of the main arguments for the anti-inflammatory hypothesis is that MSCs have a profoundly positive effect on recovery when injected in to the bloodstream. However, many of the cells that are injected this way get stuck in peripheral organs. Two of the main organs that the cells end up in are the lungs and the spleen, both of which have large resident populations of immune cells. Scientists have observed that when the MSCs stick to each organ, that they stimulate the resident immune cells to release anti-inflammatory signals that calm the body’s systemic inflammatory response. There is strong evidence that several types of stem cells beyond MSCs act directly on the spleen when delivered after stroke, and that the spleen in turn releases anti-inflammatory molecules. Many studies have demonstrated that these anti-inflammatory factors both protect from injury and promote regeneration.

On the other hand, what about when cells are injected straight into the brain, as in the recent stroke trial that I wrote about ? It has been shown in both stroke and traumatic brain injury that one of the immediate effects of injecting cells directly into the brain is to modulate the phenotype of the resident brain immune cells (called microglia). When immune cells become active, they can act either pro- or anti-inflammatory. Stroke and other neural injuries activate the microglia into their pro-inflammatory phenotype. Injecting MSCS into the brain appears to have the effect of reprogramming the microglia from being pro-inflammatory to anti-inflammatory. This reprogramming then might clear the way for brain cells to grow and thrive, which is ultimately necessary for a sufferer of a brain injury to regain function.

This work is fascinating, but with MSCs, the story is not usually so simple. I think that it is likely that MSCs act more efficiently on the brain with an intact and functional immune system, but it is doubtful that it is the sole mechanism. Too much literature exists that shows MSCs can secrete factors that have an immediate impact on the microenvironment. One thing this works does highlight, however, is that we're all integrated wholes, and that we need each of our systems to functional properly to be healthy.
​
How might all this affect you? Hopefully, none of you will have a stroke, brain injury, MS, or any other debilitating disease to deal with. But even in the absence of a specific disease, the inflammatory hypothesis could prove to be important for Forever Labs customers. As we age, many of us become chronically inflamed. Chronic inflammation correlates to everything from arthritis to Alzheimer’s to cancer. We here at Forever Labs like to envision a world in which we can use our cells to reduce systemic inflammation periodically. It remains to be seen what the optimal conditions from this type of prophylactic treatment might be, but the more data that are out there, the more it seems likely the future of medicine is in controlling the immune system. Beyond doubt, MSCs will be a big part of that equation.