IS ALL FAT CREATED EQUAL?
Fat is a very popular treatment modality in Regenerative Medicine. There have been many articles written about fat some condemning it as being far inferior to bone marrow aspirate while others give it the highest praise. The real question is where does fat (adipose tissue) lie on the Regenerative Medicine spectrum? Like many aspects in an emerging field, the studies that are mentioned need to be scrutinized further. Our many of the studies that utilize adipose tissue flawed? One of the problems that we have is that the studies concerning the use of adipose need to be more definitive. By this I mean we need a classification concerning the source of the adipose tissue. We are not just talking about the age of the patient, the location of the tissue, but also the patient’s lean body mass. The question becomes is all fat created equal or is there a major difference between patients having a different body habitus? The following two diagrams very succinctly give us a good idea of the differences in the cell content of adipose tissue between a lean and an obese patient.
These two diagrams speak volumes concerning fat cells in patients. We have known for some time that one of the major differences between obese and lean people is that the fat cells differ in size. The lean person has more cells per CC. than the obese person. If one gains weight the cells do not grow in number but increase in size. The opposite is true when one loses weight. The number of fat cells in the body is relatively constant. If a liposuction is performed than those cells are lost forever.
Typically, there is no replacing them.
The differences between obese and lean people goes much more beyond the number of cells. We do know that adipose tissue is a source of many different cells including stem cells and other regenerative cells. Remember nature works as a symphony. It utilizes many different types of cells to achieve repair (not just stem cells). If adipose tissue is a source of stem cells than logic would say that the more obese a person is the healthier they should be since overall, they have more stem cells which are available. This is where the logic is flawed. Why is it that an obese person who has belly fat has a propensity for diabetes and other diseases including an increased incidence of cancer? The answer lies in the cell profiles.
The obese patient has many more inflammatory cells. The inflammation caused by these cells leads to many medical problems. We now know that the cell profiles determine what the health of the patient might be. We look at the cell profiles in the above diagrams and can observe a significant difference in cell types.
Let us break this down further. In the second diagram we see in the lean adipose tissue anti-inflammatory cells far exceed the pro-inflammatory cells. While the obese patient has the opposite scenario.
Looking at things one cell type at a time we see the first cell to discuss is the iNKT cell. An iNKT is a type of Natural Killer T Cell (NKT). Natural killer T (NKT) cells are a heterogeneous group of T cells that share properties of both T cells and natural killer cells. NKT cells are cells that seem to be essential for several aspects of immunity because their dysfunction or deficiency has been shown to lead to the development of autoimmune diseases (such as diabetes or atherosclerosis) and cancers. They help produce a number of cytokine growth factors which help to suppress inflammation. Thus, we can see they are intimately involved in our immune system. Our immune system and stem cells are intimately intertwined. Lean fat has larger numbers of these cells compared to obese fat.
The second big difference between lean and obese fat is the in the number of M-2 macrophages. Macrophages are one of the white blood cells of the immune system. Depending upon the cell neighborhood they can either cause inflammation or reduce it.
Macrophages are found in two different activated forms called M-1 and M-2 macrophages as can be seen below.
The M-1 macrophages are macrophages which have many different names. Some people call them killer macrophages. The above diagram refers to them as the “dark side”. This is not necessarily a true identity for the M-1 macrophage. Under the right circumstances, they can save our lives by destroying invading bacteria. They are excellent in killing bacteria etc. but can cause tissue injury. The destroying of tissue is the dark side is the M-1 macrophage. Unfortunately, the inflammation is not always discriminatory. For regenerative purposes, the M-1 macrophage is not our friend. The M-2 macrophage belongs to the “Jedi Order”. The M-2 macrophage is instrumental in causing tissue repair. The “Repair" designation broadly refers to macrophages that function in constructive processes like wound healing and tissue repair, and they turn off damaging immune system activation by producing anti-inflammatory cytokines like IL-10 and TGF-beta. I liken IL-10 to the body’s cortisone with no baggage. It is one of the body’s master anti-inflammatory cytokines. The following slide is a good summation of M-1 and M-2 macrophages.
These Macrophages are also found in PRP and Bone marrow aspirate.
Another cell which is very important in the adipose profile is called a Treg cell. The regulatory T cells are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune diseases. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. T cells can cause an inflammatory response. They are responsible for many autoimmune diseases. Recent research has found that the cytokine TGF-beta is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg cells. The bottom line is that Treg cells help protect the body from various autoimmune diseases such as Rheumatoid Arthritis, Multiple Sclerosis, Diabetes, and a host of other diseases. Now we can see the reason why there is interest in studying adipose in the possible treatment of autoimmune diseases.
The Treg cells can also be instrumental in repair. A source of Treg cells along with M-2 macrophages can be a potential weapon in the treatment of autoimmune diseases. I will admit that bone marrow aspirate also contains large numbers of Treg cells.
The real question becomes is there a method that would allow us to change the profile of the fat cells? Can we make obese adipose tissue behave more like lean adipose tissue? Can we change the cell profile to have more cells which will help in repair process? Can we make these cells more effective for autoimmune diseases?
These are very intriguing questions. It appears that the answer to these questions is yes. This can be done by changing the environment of the cells. In another word, change the cytokines the cells are exposed to. The purpose of this blog is not to say that the adipose tissue from obese patients cannot have benefits but that a lean patient’s adipose tissue may have more benefits.
Changing the environment of the cells is easier said than done. Some of this can be achieved by the use of supplements (such as Nitric Oxide generators and Curcumin) which may help improve the environment of the cells. A bigger method of improving the cell profile may be accomplished by Cytokine Therapy.
Cytokines are signaling proteins that are produced by white blood cells and stem cells. They help mediate and regulate immune responses, inflammation, and repair. By the addition of certain growth factors, we can cause a preponderance of let us say M-2 macrophages and Treg cells while at the same time suppressing other types of cells which lead to inflammation. We are pointing the adipose tissue towards repair.
When looking at these cell profiles and adipose in general there are many advocates of using fat sources after they are broken down into more of their component parts. This is typically done by using an enzyme. The product produced is called SVF or stromal vascular fraction. This technique and resulting product (SVF) is currently not permitted in the United States. We do not use any SVF in our procedures given the FDA regulations. It is currently permitted in many other countries.
I am certain that the addition of the growth factors such as IL-1A and IL-10 to all types of adipose tissue may have a significant effect on the use of fat as a Regenerative modality.
Thanks, Dr. P