Celling Blog
TedSand
April 29, 2014
You can click on the link to search the archives for his other posts on stem cells.
http://www.cellingbiosciences.com/blog/archives/479
CARTOONS ARE STILL GREAT IV:
IMMUNOMODULATORY FUNCTIONS OF MSCS
I reviewed how MSCs are angiogenic and mitogenic and the role of these two trophic effects in the last post. Now I would like to continue by reviewing how MSCs are immunomodulatory.
Immunomodulation is a big topic with a lot of different effector functions. Some of these modulatory elements are important in reducing inflammation, which in turn reduces pain and scarring. The anti-inflammatory/anti-scarring effector functions were covered in this post. MSCs play a key role in managing deviations away from the homeostatic balance caused by other cells that are doing their job by reacting to signals in the body.
For example, when you step on a nail, and bacteria are introduced into the wound, it is really important to have the bacteria dealt with as soon as possible. Almost immediately, granulocytes (aka neutrophils), which are everywhere in our tissues, sense the bacterial cells and initiate a response against them by secreting factors that stimulate other protective cells, T-cells and B-cells, to migrate into the site and participate in the destruction of the foreign matter. Macrophages will be stimulated to try to engulf the bacterial particles, and B-cells will start to secrete antibodies that will bind to the bacteria, which in turn starts a cascade of complement fixation that directly results in enzymatic destruction of the bacterial cell wall. Throughout this process, which can start within minutes but can take much longer to hit its stride, bits and pieces of the bacterial particles are being stripped off and used to amplify the cellular (T-cell) and antibody (B-cell) responses, thereby hastening immune clearance of the bacterial particles.
Now, you might be wondering why we would want to impede this very important protective mechanism by having MSCs intervene. The answer is that in this situation, the innate mechanisms of survival are good if they are limited to destroying bacterial and viral invaders of our bodies. The initial response is important, but eventually the threat of bacterial infection is reduced, and the body needs to repair the damaged tissue, which is when MSCs have an important role to convert the pro-inflammatory environment over into a reparative phase, where the damaged tissue is remodeled.
I spoke collectively of T-cells and B-cells in the example above, but in reality the body’s response to a bacterial invasion is incredibly complex. For example, there are quite a few cell types involved in the example described above, including T-cells (helper T-cells, cytotoxic T-cells, Treg cells, etc), B-cells, NK cells, dendritic cells, monocytes, macrophages, and the ever-present granulocytes. Each of these cell types plays an important role in mounting an immune response, but the problem comes when the same functions are applied to tissue trauma.
So, let’s take another example. You have an early on-set osteoarthritic condition in your knee. There is mild inflammation, because the cartilage is wearing out and the microscopic bits and pieces of tissue stimulate a clearance mechanism by macrophages and/or granulocytes—just like if there were bacterial particles present. The wear and tear in your knee results in cleanup procedures that further stimulate cells to migrate into the joint and do additional cleanup, which creates a cycle that over time can result in a very painful, arthritic joint.
One of the consequences of an arthritic joint is pain, since there is an abundance of biochemicals like IL-1 and TNF-α floating around, which promote inflammation and pain. Autologous progenitor cell therapy has been shown in a placebo-controlled, double blind clinical study to have statistically significantly reduced pain in arthritic joints in canine patients, which means that the MSCs present in the cell preparations are working via a number of mechanisms to reduce inflammation and associated pain.
One way to reduce inflammation (and pain) in an arthritic joint is to reduce recruitment (by a process called chemotaxis) of cells like macrophages and granulocytes into a pathologic site, which MSCs are able to do. Furthermore, MSCs are able to reduce the proliferation of B-cells, marcophages and other cells that have already arrived in the arthritic joint, resulting in a reduction in the number of cells present that can secrete pro-inflammatory factors.
So, MSCs can modulate the impact of cells of the immune system by secreting a variety of biochemical factors, which shut down the immune cells from secreting pro-inflammatory molecules, reducing chemotaxis and reducing the proliferation of cells already present in the arthritic joint. The net effect is that a less caustic environment is created in the joint, which is associated with less pain and a heightened potential for regenerative repair of the degraded tissue. Details concerning mechanisms and specific factors involved in the immunomodulatory effector function of MSCs can be found in a recent review by Murphy, et al.
What I tried to do in this post is stick to pathologies, like osteoarthritis, which are amenable to being treated with your own MSCs, as found in bone marrow concentrate. Of course, there are a number of companies who are trying to demonstrate effective outcomes with cultured cells, but none of these therapies are cleared as yet and most have a long way to go before being cleared for use in the US.
I will cover the last biological effector function associated with MSCs, anti-microbial activity, in the next post.
TedSand
April 29, 2014
You can click on the link to search the archives for his other posts on stem cells.
http://www.cellingbiosciences.com/blog/archives/479
CARTOONS ARE STILL GREAT IV:
IMMUNOMODULATORY FUNCTIONS OF MSCS
I reviewed how MSCs are angiogenic and mitogenic and the role of these two trophic effects in the last post. Now I would like to continue by reviewing how MSCs are immunomodulatory.
Immunomodulation is a big topic with a lot of different effector functions. Some of these modulatory elements are important in reducing inflammation, which in turn reduces pain and scarring. The anti-inflammatory/anti-scarring effector functions were covered in this post. MSCs play a key role in managing deviations away from the homeostatic balance caused by other cells that are doing their job by reacting to signals in the body.
For example, when you step on a nail, and bacteria are introduced into the wound, it is really important to have the bacteria dealt with as soon as possible. Almost immediately, granulocytes (aka neutrophils), which are everywhere in our tissues, sense the bacterial cells and initiate a response against them by secreting factors that stimulate other protective cells, T-cells and B-cells, to migrate into the site and participate in the destruction of the foreign matter. Macrophages will be stimulated to try to engulf the bacterial particles, and B-cells will start to secrete antibodies that will bind to the bacteria, which in turn starts a cascade of complement fixation that directly results in enzymatic destruction of the bacterial cell wall. Throughout this process, which can start within minutes but can take much longer to hit its stride, bits and pieces of the bacterial particles are being stripped off and used to amplify the cellular (T-cell) and antibody (B-cell) responses, thereby hastening immune clearance of the bacterial particles.
Now, you might be wondering why we would want to impede this very important protective mechanism by having MSCs intervene. The answer is that in this situation, the innate mechanisms of survival are good if they are limited to destroying bacterial and viral invaders of our bodies. The initial response is important, but eventually the threat of bacterial infection is reduced, and the body needs to repair the damaged tissue, which is when MSCs have an important role to convert the pro-inflammatory environment over into a reparative phase, where the damaged tissue is remodeled.
I spoke collectively of T-cells and B-cells in the example above, but in reality the body’s response to a bacterial invasion is incredibly complex. For example, there are quite a few cell types involved in the example described above, including T-cells (helper T-cells, cytotoxic T-cells, Treg cells, etc), B-cells, NK cells, dendritic cells, monocytes, macrophages, and the ever-present granulocytes. Each of these cell types plays an important role in mounting an immune response, but the problem comes when the same functions are applied to tissue trauma.
So, let’s take another example. You have an early on-set osteoarthritic condition in your knee. There is mild inflammation, because the cartilage is wearing out and the microscopic bits and pieces of tissue stimulate a clearance mechanism by macrophages and/or granulocytes—just like if there were bacterial particles present. The wear and tear in your knee results in cleanup procedures that further stimulate cells to migrate into the joint and do additional cleanup, which creates a cycle that over time can result in a very painful, arthritic joint.
One of the consequences of an arthritic joint is pain, since there is an abundance of biochemicals like IL-1 and TNF-α floating around, which promote inflammation and pain. Autologous progenitor cell therapy has been shown in a placebo-controlled, double blind clinical study to have statistically significantly reduced pain in arthritic joints in canine patients, which means that the MSCs present in the cell preparations are working via a number of mechanisms to reduce inflammation and associated pain.
One way to reduce inflammation (and pain) in an arthritic joint is to reduce recruitment (by a process called chemotaxis) of cells like macrophages and granulocytes into a pathologic site, which MSCs are able to do. Furthermore, MSCs are able to reduce the proliferation of B-cells, marcophages and other cells that have already arrived in the arthritic joint, resulting in a reduction in the number of cells present that can secrete pro-inflammatory factors.
So, MSCs can modulate the impact of cells of the immune system by secreting a variety of biochemical factors, which shut down the immune cells from secreting pro-inflammatory molecules, reducing chemotaxis and reducing the proliferation of cells already present in the arthritic joint. The net effect is that a less caustic environment is created in the joint, which is associated with less pain and a heightened potential for regenerative repair of the degraded tissue. Details concerning mechanisms and specific factors involved in the immunomodulatory effector function of MSCs can be found in a recent review by Murphy, et al.
What I tried to do in this post is stick to pathologies, like osteoarthritis, which are amenable to being treated with your own MSCs, as found in bone marrow concentrate. Of course, there are a number of companies who are trying to demonstrate effective outcomes with cultured cells, but none of these therapies are cleared as yet and most have a long way to go before being cleared for use in the US.
I will cover the last biological effector function associated with MSCs, anti-microbial activity, in the next post.