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Mesenchymal Stem Cell or Medicinal Signaling Cell

Caplan first introduced the term “Mesenchymal Stem Cell” in 1991.  Here they and others had previously experimented with cells that could differentiate into bone, cartilage, tendon, and ligaments, fat, skin and muscle in laboratory studies.  This was the basis for development of the term “Mesenchymal Stem Cell” which corresponded with cells derived from the mesodermic layer in an embryo that were programmed to form all of the above noted structures in a developing embryo.  In this writing he also theorized a potential medicinal use for these cells in damaged areas of the body.

During the year of this 1991 publication, the term “Mesenchymal Stem Cell” was only found in 6 publications.  The term has quickly gained attention over the past 3 decades and can now be found in nearly 4,000 publications.  This has caused a heightened awareness amongst medical societies and governmental regulatory agencies as the term “Mesenchymal Stem Cell” appears to be used very loosely in advertisements to consumers and in publications alike.

Let’s clear the air a bit and try to understand exactly what “Mesenchymal Stem Cells” are reported to do in the studies.  The initial thought that these cells were able to differentiate into many different tissue types within the body has not been proven en vivo.  This means that there have been no strong studies proving that these cells will turn into the desired tissue if injected or administered to a site of injury.  Researchers have been able to drive differentiation of cells toward a specific cell type, like cartilage; however, this has only been done en vitro (not within the body).  There appears to be a strong sentiment within advertisements and opinions alike, that these cells will go to a site of injury and transform into the desired tissue that will then go on to repair and regenerate the area.  This has led to confusion and misconceptions about what these cells can do.  Because of this there was a recommendation made by The International Society of Cellular Therapy to abandon this term and label these cells “Multipotent Mesenchymal Stromal Cells” in 2006.  In fact Caplan, the author of the original publication labeling these as Mesenchymal Stem Cells, has asked for the term to be abandoned as well.  He has recommended they be called “Medicinal Signaling Cells” as he feels these should not be considered stem cells, which is a designation that Embryonic Stem Cells and Hematopoetic Stem Cells have and denotes that they are capable of serial transplantation and unlimited doublings.

 

What do Mesenchymal Stem Cells or Medicinal Signaling Cells do?

In the body, these cells appear to migrate toward sites of injury after being mobilized from areas like bone marrow through blood vessels.  Upon reaching the site of injury or inflammation, these cells appear to secrete bioactive factors that have therapeutic effects to include being immunomodulating and trophic (regenerative) effects.  Some of these bioactive factors include TGF-Beta, EGF, IGF-1 and VEGF to name a few.  These appear to have downstream effects, which include recruiting local cells in the area of injury or inflammation to undergo repair and regeneration and improve vascularity in these regions.  They can also decrease inflammation by inhibiting immune cells in the region that cause the inflammation.

 

What are potential benefits of Mesenchymal Stem Cells or Medicinal Signaling Cells?

Clinical studies looking at the effects of MSC at sites of injury or inflammation have been performed across numerous fields in medicine.  Within the orthopedic field the studies tend to be of a low quality level of evidence and are sometimes hard to draw conclusions from.  Because of this most insurance companies still consider treatments to be experimental and as such have denied coverage for them.

Fracture healing: It has long been known that bone marrow aspirate can aide with fracture healing at sites of non-union or delayed union.  Medicinal Signaling Cells injected at these sites appear to aide with fracture healing in several studies.

Osteonecrosis of hip: Investigators have looked at MSC injections for treatment of early stage osteonecrosis of the hip.  In some of these studies the patients that had bone marrow aspirate, containing the Medicinal Signaling Cells (Mesenchymal Stem Cells), injected into the bone after a decompression was performed demonstrated more reduction in pain and symptoms and perhaps a delay or avoidance in progression of the disease.

Osteoarthritis of knee: Several studies have demonstrated improvements in patient reported outcomes and perhaps improvement in cartilage damage.  A common limitation amongst these studies is the lack of a control group.  The concept of mesenchymal stem cells (medicinal signaling cells) having a desired treatment effect on an osteoarthritic knee has been demonstrated by Jo and colleagues in 2014.  There are several clinical trials looking at these effects underway.

 

What are sources of Medicinal Signaling Cells (Mesenchymal Stem Cells)?

In 2006 the International Society for Cellular Therapy released a position statement with regards to Mesenchymal Stem Cells, or as they would prefer to be termed Multipotent Mesenchymal Stromal Cells, or as Caplan would prefer to be termed Medicinal Signaling Cells.  In this publication, the society adopted minimal criteria for what defines an “MSC” which revolved around what proteins need to be absent and present on these cells.  They must have CD105, CD73 and CD90.  They must not have CD45, CD34, CD14, CD11b, CD79alpha, CD19 or HLA-DR surface molecules.

Autograft (from your own body): These cells are routinely harvested from your own bone marrow.  The most common source is the iliac crest, or the prominent portions of your pelvis.  Fat has also been used as a source for these cells. 

Allograft (from someone else’s body): There are several formulations of allograft products on the market.  Bone marrow aspirate from a cadaver has been found to yield viable MSC.  Amniotic fluid preparations are marketed to contain cells; however, recent studies have found no significant amount of viable MSC in several of these products.  They do appear to contain growth factors that may play a role in healing at sites of injury.  Other forms of birth-related regenerative therapies include umbilical cord derived cells from Wharton’s Jelly or the cord lining.  These products appear to have some cellular material; however, there is uncertainty as to whether or not these cells meet the standard definition of an MSC set forth by the International Society of Cellular Therapy.  The other underlying question around these products is whether or not there are any viable cells left after processing and storage.

 

Are there potential adverse effects with Mesenchymal Stem Cells (Medicinal Signaling Cells)?

There can be local pain at the injection site or site of harvest if using your body’s own cells.  More serious; however, exceedingly rare complications could include an infection.

When using allograft products such as those derived from umbilical cord or amniotic fluid preparations, there are more challenges posed.  One of the main ones is the risk of contamination of these products with bacteria as highlighted in a recent series of serious infections in patients after receiving injections from contaminated products.  This was reported in a recent Washington Post article and prompted further investigation into some of the companies with a subsequent warning to the companies by the FDA. 

Lastly, MSC have been proposed to be immunoprivileged, or not capable of mounting a significant immune effect.  This comes down to proteins on the cells known as HLA Class I and HLA Class II antigens.  In transplant surgeries, these antigens need to match closely with your body’s own antigens, otherwise there will be a failure of the transplant.  Although these antigens are found at low levels on these MSC, they still are detectable.  There have been several cases of allogeneic MSC rejection and chronic immune responses in animal and clinical studies.  This is not a concern when the MSC are derived from your own body as in bone marrow or fat.

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  11. Mancuso, P., Raman, S., Glynn, A., Barry, F. & Murphy, J. M. Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role of the Cell Secretome. Front. Bioeng. Biotechnol. 7, 1815 (2019).
  12. Robinson, P. G. et al. Reporting of Mesenchymal Stem Cell Preparation Protocols and Composition: A Systematic Review of the Clinical Orthopaedic Literature. The American Journal of Sports Medicine 47, 991–1000 (2019).
  13. Panero, A. J., Hirahara, A. M., Andersen, W. J., Rothenberg, J. & Fierro, F. Are Amniotic Fluid Products Stem Cell Therapies? A Study of Amniotic Fluid Preparations for Mesenchymal Stem Cells With Bone Marrow Comparison. The American Journal of Sports Medicine 47, 1230–1235 (2019).
  14. FDA sends warning to companies for offering unapproved umbilical cord

            blood products that may put patients at risk.  – FDA Press Release         12/06/2019

  1. ‘Miraculous’ stem cell therapy has sickened people in five states. – Wan, W., McGinley, L.  The Washington Post, 2/27/2019