Mesenchymal Stem Cells [MSCs]

There are some who hypothesize that MSCs may not even be considered stem cells. First is the realization that this class of cells can be isolated from almost every tissue in the human body.

The central connecting aspect to explain this fact is that all of these tissues are vascularized and that every blood vessel in the body has mesenchymal cells in abluminal locations. These perivascular cells can thus be called Pericytes and some of these cells become MSCs upon focal injury.

By secreting factors that mute the immune system, the MSC-pericytes inhibit T-cell surveillance of the damaged tissue and bioactive agents are released by MSCs that establish a regenerative microenvironment.

Factors secreted by MSCs are mitotic to tissue-specific progenitors that add to tissue regeneration.

Mesenchymal stem cells are being used therapeutically because they undergo homing to sites of inflammation or tissue injury and they secrete massive levels of bioactive agents that are both immunomodulatory and trophic.

Caplan states “I would suggest that MSCs are powerful site-regulated DRUG STORES or dispensing sites that may serve as modulatory or curative agents for a variety of human maladies. Since the multipotency of MSCs is not the key aspect for their current therapeutic use, I herein propose a name change: MSC = Medicinal Signaling Cells”.

MSCs and the Immune System

The immune system consists of two major parts, T-1 and T-2.

T-1 is called Cell-mediated immunity is an immune response that does not involve antibodies, but rather involves the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

T-2 is called Humoral immunity and is the aspect of immunity that is mediated by macromolecules found in extracellular fluids such as secreted antibodies, complement proteins, and certain antimicrobial peptides. Humoral immunity is so named because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Its aspects involving antibodies are often called antibody-mediated immunity.

Pain Management

Mesenchymal stem cells make molecules that occupy opioid receptors. They are effective in the central and peripheral nervous system: reducing inflammation and enhancing regenerative activity as well as reducing pain.

There are numerous publications verifying that MSCs can control or affect pain.

White Fat

White fat is most plastic adipose tissue and represents a very suitable source of stem cells.

In addition to mesenchymal stem cells, it contains large population of hematopoietic cells composed of macrophages and hematopoietic progenitor cells. White fat cells can also give rise to osteoblasts, endothelial cells, adipocytes and cardiomyoblasts.

Stromal Vascular Fraction

The Stromal Vascular Fraction [SVF] is taken from adipose (fat) tissue and contains multiple cell types. Again, one of the most important cell types is the mesenchymal stem cell. As indicated above, MSCs are very specialized and will cause immune modulation in the body, correcting many vexing conditions. For example, treatments using these cells have achieved very successful results with auto-immune diseases, including osteoporosis and various forms of arthritis, degenerative orthopedic conditions and lung diseases. There have also been reported good results with eye diseases, brain issues, Crohn’s disease, Hashimoto’s Thyroiditis, trauma and a range of other conditions.

SVF Composition

Stromal Vascular Fraction is the freshly isolated heterogeneous cell fraction derived from fat. It is composed of many mature, progenitor and stem cell types, including:

Mesenchymal stromal/stem cells [MSCs]

Hematopoietic stem cells [HSCs]

Hematopoietic progenitor cells.

Endothelial progenitor cells [EPC]

Pericytes

Pre-adipocytes

Adipocytes

M2 Monocytes/macropharges

Regulatory T-cells

Vascular progenitors

Fibroblasts

Smooth Muscle cells

Depending on the processing method used and various other factors, the proportion of SVF components can range considerably, as the following indicates:

Phenotypical Components [Cell Markers]

Other cells in SVF include CD13, CD29, CD36, CD44, CD104a, CD106, CD140b and CD144.

Adipose-Derived Stromal/Stem Cells ASCs

*Adipose-derived stromal/stem cells [ASCs] is a term used to identify the isolated, plastic-adherent, multipotent cell population in an SVF sample. It is sometimes referred to as MSCs isolated from the adipose tissue. ASCs can be phenotypically identified as CD45− CD235a− CD31− CD34+ and they differ from bone‐marrow‐derived MSCs in their positivity for CD36 and negativity for CD106.

Progenitor Cells

Progenitor cells are often referred to as transit-amplifying or transiently amplifying cells. They differ from stem cells in that they are not self-renewing, short lived and have a high proliferative capacity. Stem cells have the opposite characteristics.

Endothelial Progenitor Cells, EPCs

EPCs are initially required for early embryo development. In adults, vascular growth develops from fully‐differentiated endothelial cells. Hence, EPCs are used in the treatment of diseases with a pathogenic vascular component. Numerous clinical trials have been conducted in patients with heart disease, diabetes, peripheral arterial disease, pulmonary disease, and cancer, where putative EPCs have been examined as a biomarker or used as cell therapy.

There is an EPC subset that has been shown to express genes involved in inflammation and immune responses. This can be minimized by the techniques for harvesting fat.

Note that EPC circulating and wound level numbers are decreased in diabetes. So, for diabetic patients, special measures are needed prior to treatment.

Monocytes and Macrophages

Macrophages have prominent plasticity and are classified into activated M1 or activated M2 macrophages, depending on the specific micro-environment they are in.

M1 macrophages are pro-inflammatory and possess remarkable antimicrobial abilities via the secretion of various inflammatory cytokines and chemokines.

M2 macrophages are immunomodulatory by releasing IL-10 and trophic factors to promote tissue repair and resolve inflammation.

Modulating macrophages toward an M2 phenotype has been associated with significant protection against atherosclerosis, for example. A 2015 clinical trial showed that stroke patients who received autologous M2 macrophages significantly improved their neurological recovery, in part through the immuno-modulatory activity of M2 macrophages.

Studies indicate that monocytes/macrophages present in fatty tissue are significantly affected by obesity. In obese patients there was a significantly higher occurrence of M1 phenotype, closely associate with chronic inflammation in part by producing pro‐inflammatory molecules. The effect is more marked in insulin‐resistant patients. Accordingly, special measures have to be taken before fat is harvested from obese persons so as to reduce the extent or effect of M1 composition.

Interestingly, post-bariatric surgery patients displayed reduced M1 accumulation compared to pre-surgery levels, supporting the notion that the inflammatory environment is driven by adipose accumulation.

Regulatory T‐cells

All T-cells come from progenitor cells from the bone marrow, which become committed to their lineage in the thymus. The immune system must be able to discriminate between self and non-self. When self/non-self-discrimination fails, the immune system destroys cells and tissues of the body and, as a result, causes autoimmune diseases.

Regulatory T‐cells (Tregs) are an immuno-suppressive subpopulation of T‐cells. These cells inhibit the induction/proliferation of effector T‐cells, thereby modulating allergic responses, autoimmunity, inflammation and responses to infections and tumors. Tregs derived from fat comprise approximately 50%–70% of the CD4+ T‐cell compartment and contain a much higher [136 fold] level of IL‐10 compared to lymph node Tregs. This indicates a higher anti‐inflammatory potential for fat‐derived Tregs. Again though, the negative effects of obesity are also observed in these cells.

The immunosuppressive cytokines, TGF-beta and Interleukin 10(IL-10), have also been implicated in regulatory T-cell function [see the Cytokine page].

Tregs may be generated in response to TGF-β and IL-10. As a result, the immune response will be inhibited and local inflammation is suppressed.

Pericytes

Blood vessels throughout the body are formed by two interacting cell types: endothelial cells and perivascular cells. Pericytes are essential for development of the vascular system. Amongst other things, they regulate blood flow by modulating vasoconstriction and vasodilation. The highest density of pericytes is found in vessels of the central nervous system, where endothelial cells are covered with pericytes in a 1:1 to 3:1 ratio to form and protect the blood‐brain barrier.

In the liver, they are called hepatic stellate cells and are known to regulate extracellular matrix remodeling, vitamin A metabolism (containing more than 80% of the total vitamin A in the body) and inflammatory cell recruitment resulting from liver diseases.

Studies have shown that adipose‐derived pericytes have significant bone regeneration potential and have increased the lifespan of patients with Duchenne muscular dystrophy.

Stress conditions significantly affect pericyte survival. Loss of pericytes is an early hallmark of diabetic retinopathy and leads to micro-aneurysm due to reduced vessel integrity and neuronal degeneration.

Clearly, pericytes have a therapeutic role, particularly for the treatment of diseases with a vascular component, given their critical role in vascular structure and function.

Potential Applications for Fat Derived Cells

This list is not exhaustive.