Stem Cells and the Immune System (Part II)
June 18, 2017
In part one we have discussed various effects that the stem cells have upon the immune system. Various stem cells will help in the release of certain type of immune cells. Some of these cells will stimulate an immune response while other will diminish the immune response. We are still missing one very important effect that they have on what we call macrophages and other cells.
As was mentioned in part one of the most important stem cells in dealing with the immune system is the mesenchymal stem cells (MSCs). As Dr. A Caplan states they are “medicinal signaling cells”. Their main function is not to cause tissue regeneration but to help in immunomodulation. In another word, they help water down an immune response. Without these cells, most repair would never be accomplished the area and the damaged area would remain unrepaired. The following diagram from one of my lectures is an excellent description of these cells:
As you can see like Navy Seals they are very specialized. They will not win the war but they can secure an area so that other forces (stem cells) can come in an accomplish repair. MSCs possess broad immunomodulatory properties. After activation, MSCs can secrete a variety of soluble factors, such as NO, IDO, PGE2, TGF-β, HLA-G5, TSG-6, CCL2, IL-1Ra, and IL-10. These are various growth factors or cytokines that are produced. Their names are not that important to the lay person. What we really need to know is that production of these factors can suppress the differentiation, proliferation, activation of various immune cell subsets. As a result, the immune response will be inhibited and local inflammation is suppressed by MSCs.
One effect of the MSCs that has not been mentioned is the effect that they have on macrophages. The Wikipedia definition of macrophages “Macrophages are a type of white blood cell that engulfs and digests cellular debris, foreign able to be accomplished. The body would destroy all reparative cells substances, microbes, cancer cells, and anything else that does not have the types of proteins specific to healthy body cells on its surface in a process called phagocytosis”. However, there is more than meets the eye here. The following slide from another of my lectures shows the importance of macrophages:
What we are able to ascertain from this diagram is that there are two types of macrophages. The following slide is an explanation of these two types of macrophages.
The MSCs will affect the microenvironment which ultimately determines the fate of the development of the macrophage. Obviously when we are fighting an infection we want to produce the M-1 type of macrophage to obliterate an infection. However, when we are performing a regenerative medicine procedure we want to produce an M-2 macrophage which will help with immune modulation. Anything we can do to help the MSCs will be a boon to regeneration. You may ask how do we do this very simply. If you were to look at the diagram you will see some growth factors with the following designations IL-1a, IL-10, and TGF-b. These are powerful growth factors that will nip inflammation in the bud. These are part of our propriety cytokine formulas. We are helping the regeneration. We are encouraging the release of M-2 macrophages which are immunomodulatory and also release growth factors which promote tissue repair. This is one reason why we do not feel it is wise to eliminate white blood cells of which macrophages are a part of that family from a Platelet Rich Plasma (PRP) mixture. We are also able to produce more M-2 macrophages by a process of photo-modulation. This occurs when a PRP product treated with certain wavelengths of light increases M-2 macrophage production. Macrophages are also important for other purposes. They help with what is called stem cell homing.
One more effect that the stem cells have upon the immune system involves the production of LL-37. LL-37 is a very interesting compound. It is one of the most effective anti-microbial compounds known to man and actually the only antimicrobial produced by man. It gives broad antimicrobial protection against bacteria, fungi and viruses. Human bone marrow-derived MSCs possess direct antimicrobial activity, which is mediated in part by the secretion of human cathelicidin LL-37. Another interesting fact is that the effect of Vitamin D-3 on the function of LL-37 and chemokine production as well as an important role in immunomodulation. These anti-inflammatory and anti-infective roles of Vitamin D are becoming increasingly important.
The actual mechanism of LL-37 production is thought to be turning on a gene which helps production of LL-37. The vitamin D turns on this gene. Is there any practical example of the relationship between stem cells, vitamin D and the immune system? Perhaps one of the best examples occurs when a woman has a period. During a menstrual period, there is a setup for an infection. We have bacteria present in the mist of blood products at a temperature conducive for bacterial growth. This is a recipe for infection. Yet infection almost never occurs. Why is this so? We must remember one thing. Menstrual blood is very rich in mesenchymal stem cells. These mesenchymal stem cells release compounds including LL-37 which will luckily squash any type of infection. I have just scratched the surface concerning stem cells and our immune system but I believe we see how these important stem cells may be used in the treatment of many different conditions. Thanks Dr. P
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