Let us begin with the very basics; MSC is the acronym for Mesenchymal Stem Cells. A MSC is a type or sub set of adult stem cells. They have been found in many tissues of the human body including but certainly not limited to bone marrow, cord blood, amniotic fluid and even the fatty tissue known as adipose. MSC derived from bone marrow are referred to as ‘nonhematopoietic stromal cells’ and those derived from the Umbilical Cord are simply referred to as Cord Blood Mesenchymals.
Observations made over 130 years ago by German pathologist Cohnheim brought to light the first hint of MSC’s. He noted in his observations of wound repair the possibility that bone marrow might be a source for collagen fibers created by fibroblast cells. This concept lay for the most part doormat within the journals of science until the 1970’s when another scientific explorer Friedenstein along with his team took a bit of bone marrow and placed it in a plastic dish. Then with a very simplistic separation process found that cells from the marrow culture were creating colonies and taking on the characteristics of bone and cartilage cells.
MSC’s within the umbilical cord are actually one of the rarer subsets accounting for only 1 in 10,000 or less of the total nucleated cells. However they can be found in greater numbers within the marrow making bone marrow aspiration an ideal way to collect Mesenchymal Stem Cells. Even still the total number that can be collected from either the marrow or the cord is too low in quantity to provide a substantial therapeutic dose for reinfusion. However MSC’s can be expanded in number through culturing and this expansion of MSC can be done many times over while still retaining their quality and versatile ability to differentiate.
Studies in animals have shown that MSC’s when given systemically as would be the case with an intravenous transfusion have a remarkable ability to migrate or move to areas of damage. This is known as “migratory capacity”. Chemicals released by damaged or stressed tissues known as Chemokines also play a significant role in the migratory ability of MSC’s [8]. Studies have shown that there are receptor sites for Chemokines on the exterior of a Mesenchymal Stem Cell which act like a magnet attracting the cells to areas of higher concentrations of Chemokines and thus drawing them to damaged tissues.
MSC’s have the ability to differentiate into such tissue types as bone, cartilage, muscle cells (skeletal myocytes), ligament and tendon tissue as well as of course that fatty tissue we politely call adipose (adipocytes). One study conducted by the team of Wakitani, Caplan and Saito done in 1995 using rat bone marrow which was treated with the substances known as 5-azacytidine and amphotericin B resulted in MSC’s that differentiated into Myoblasts. These cells then fused into rhythmically beating myotubes. This is key point of research which may lead to the ability to someday treat and/or repair such tissues as the human heart. Mesenchymals have also been differentiated into pericytes (smooth muscle cells) as well as thymic stroma.
In one study hMSC’s were transplanted into fetal sheep during early gestation prior to the full development and activation of the immune system. Examinations done as long as 13 months post implantation reveled the cells to be present in numerous tissue types within the sheep [5]. Microscopic examination of the various tissues showed that the MSC’s had under gone site-specific differentiation meaning that the transplanted cells changed and developed into cell types similar to those host cells they were in physical contact with. This is a critical point of importance when applying this type of technology to humans. Later examinations showed that even after the development of the sheep’s immune system the cells were still present in many tissue types. This study demonstrates that the hMSC’s did not trigger a reaction from the host’s immune system.
An earlier study completed the year prior [6] utilizing murine MSC’s which were injected into the back portion of the brains of 3 day old mice yielded evidence that the transplanted cells had migrated to the forebrain and cerebellum just 12 days later. Post mortem examination reveled that some of the cells had differentiated into neurons as evidenced by their expression neurofilaments. An interesting but debated piece of work was done in the year 2000 by researchers Woodbury, Schwarz and Prockop. They utilized both rat and human bone marrow stromal cells and reported their ability to differentiate into neuron-like cells which expressed similar external markers seen in mature neurons. The debate arose two years later in 2002 when another team lead by CP Hofstetter working in a similar fashion found that the neural-like cells lacked the voltage-gated ion channels necessary for the generation of action potential. This meant that while appearing on the outside to be a neuron internally the cells could not generate an impulse and thus were not true neurons. The issue remains undetermined with researchers falling on both sides of the fence.
What is not debated and of great interest is the immunosuppressive ability of the MSC. There have been many studies reporting modulation of T-cell activity by MSC’s [1, 2]. Human MSC’s (hMSC) have been have shown to improve hematopoietic engraftment in a study conducted in 2005 by researcher HM Lazarus. This came after the 2004 report by K Le Blanc that human MSC’s could be used to treat graft versus host disease. Now just four years later this is a heavily researched area and the use of hMSC’s is becoming more common within many countries as a method of treatment for this disease.
For those with Multiple Sclerosis (MS) and other autoimmune disorders take note of another critical point; that this capacity of the MSC’s to suppress T-cell function has lead to a possible treatment for disorders such as encephalomyelitis [3]. Encephalomyelitis is considered to be a scientific model for MS in research as both are disorders involving self reactive T-cells. MSC administration was shown to improve disease symptoms greatly in affected mice studies conducted by Zappia’s team.
Of note for suffers of Arthritis was a study conducted in 2005 by lead researcher F Djouad studying the immunosuppressive properties of MSC’s in collagen-induced arthritis (CIA) a common research model for Rheumatoid Arthritis (RA). The work concluded that MSC’s offered no benefit for CIA. In fact Djouads team showed an increase in the Th 1 response of the treated host.
In 2002 a team studying the affect of MSC’s on spinal cord injury’s injected paraplegic rats with rat derived MSC’s one week post induced injury [4]. Post treatment dissection showed that the cells had migrated to the injury site and formed new bundle fibers thus closing the gap at the injury site. This clearly indicated regeneration at the area of the spinal cord lesion and further showed that differentiation into the specific cell type may not in fact be necessary to result in clinical benefit. Improvement within the patient may actually be gained as a result of the MSC implantation inducing production of local growth factors which aid in healing of the injured cells and the benefit of the structural formation of strands bridging the gap in the area of injury.
Research into the mechanisms of actions of Mesenchymal Stem Cells is still ongoing and much of their apparent magical abilities will no doubt be unveiled to us in the years to come. They have already proven themselves to be hardy and versatile as well as clinically beneficial. Their most fascinating and promising attribute is their immuno suppressive quality. This trait may mean that when used in combination with other sub sets of stem cells the MSC’s could enhance the administration and engraftment of these other cells. There might even come a day when Mesenchymal Stem Cell’s will be able to act as carrier molecules in the delivery of other therapeutic interventions.
- Di Nicola M, Carlo-Stella C, Magni M. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002.
- Bartholomew A, Sturgeon C, Siatskas M. MSC’s suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 2002.
- Zappia E, Casazza S, Pedemonte E. MSC’s ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 2005
- Hofstetter CP, Schwarz EJ, Hess D. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA 2002.
- Liechty KW, MacKenzie TC, Shaaban AF. Human MSC’s engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 2000.
- Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout the forebrain and cerebellum and differentiate into astrocytes after injection into mouse brains. Proc Natl Acad Sci USA 1999.
- Baggiolini M. Chemokines and leukocyte traffic. Nature 1998.