MESENCHYMAL STEM CELLS
LAY REVIEW

INTRODUCTION
Advancements in science and technology have changed the way we look at the world. We’ve put a man on the moon and cloned a sheep, but what about the medical potential of our own bodies? Is there a way to fight off death and disease while maintaining balance throughout? What about the idea of universal cells – master keys that fit everyone’s different immunological locks – that react and adapt to better our state of being?

Mesenchymal stem cells (MSCs) are commonly labeled the “duct tape” of the immunological “toolbox” for their ability to be used in many circumstances. In general, MSCs normally differentiate along a mesodermal lineage generating bone, cartilage, muscle and fat (Figure 1). Scientific evidence has also demonstrated that MSCs can further form cells of different lineages to generate neurons, cardiomyocytes, and muscle cells.  (Mangi, 2003, Ferarri, 1998, Azizi, 1998)

Figure 1: Mesenchymal Stem Cell Lineages

MSCs are commonly harvested from the bone marrow – the bone marrow being the body’s immunological mecca – but can also be found in other organs including the fetal lung and fetal liver. MSCs surround the central sinus of the bone marrow where they favor the high-oxygenated environment (Figure 2). MSCS can be identified by testing positive for various biological markers, CD44, CD105, CD29 (cluster of differentiation).  These molecules are a marked identification that alerts scientists of the characteristics of cell and allow them to identify the cell’s presence among numerous other cells.

Figure 2: Bone Marrow Niche

The potential of MSCs has only been discovered recently, but their immunological characteristics have been noted for decades. The first documented occurrence of an immunological response via MSCs was published by Julius Cohnheim, a German pathologist. In 1867, Cohnheim proved that the emigration of white blood cells is the origin of pus, the body’s inflammatory response to bacterial infection. Cohnheim at the time was working under the tutelage of Dr. Rudolf Virchow, a well-known pathologist who was accredited as the first to recognize leukemia and its effect on white blood cells.
In 1970, Alexander Friedenstein acknowledged the growth of fibroblasts (structural cells) in cultures of guinea pig bone marrow and spleen cells and later published his findings. This supported the idea that MSCs and their committed progenitors (forming function) develop CFU-F (Colony Forming Units-Fibroblast) (Bianco, 2001).

Isolation and Expansion of MSCs

Mesenchymal Stem Cells and Plasticity

Some scientists believe that MSCs show plastic properties.  For a stem cell to be plastic is to mean that the cells ultimately become different from what is expected.  This is done in the laboratory by simulating an environment of another type of cell.  The original intent is to generate mesenchymal lineages. MSCs are thought to be plastic because scientists have seen MSCs cross a lineage barrier and make cells other than the original intent. However, scientists have reported that MSCs can repair, and possibly take on the properties of heart-like cells, muscle-like cell, and neuronal-like cells (Mangi, 2003, Ferarri, 1998, Azizi, 1998).  The finding that MSCs could repair or turn into neuronal-like cells is very unusual, since neuronal cells are developed in a completely different pathway during fetal development.  Scientists remain skeptical about plasticity because the experimentation techniques are difficult to reproduce in different laboratories, such as the use of different culture media and variation in length of culture.  Also, our current models of stem cell lineages do not allow for plasticity.  For example, it was reported that MSCs and hematopoietic stem cells could originate from the same source (Huss, 2000).  This indicates that perhaps the stem cell lineages are not fully mapped and provide many areas for future research.

Current and Future Clinical Applications

Organ Generation / Transplants

MSCs have been shown to produce cells from its own lineage, such as bone, cartilage, muscle, ligament, tendon, fat, stroma, and cells from non-MSC-lineage,  under specific laboratory conditions, such as pancreatic, kidney, heart and brain cells. If MSCs can produce cells for a specific organ outside of the body, could they be engineered to generate an actual organ? Currently, scientists are trying to answer that question by manipulating MSCs in the laboratory to determine what cells they could differentiate to, besides what is expected. The ability to grow organs, or even large amounts of cultured tissue, would prove extremely beneficial in many different medical and scientific fields.  For instance, in the pharmaceutical industry, new drugs and treatments could be tested on actual human cells. This could eliminate the use of animal models, cutting costs and saving the lives of numerous laboratory animals. Furthermore, if these organs could be produced by the recipient or as universally recognized tissue, rejection and Graft Versus Host Disease could be avoided. Graft Versus Host Disease occurs in some patients after a transplant due to the immune system of the donor attacking the recipient cells.  If we could avoid the possibility of rejection, this would eliminate the need for transplantation matching, thereby rendering expensive and time-consuming transplantation lists unnecessary. 

Regarding the immune properties, there are several studies which show that a small dosage of MSCs in the area of transplantation will decrease the probability and/or severity of Graft Versus Host Disease. There have been positive results from clinical trials studying the affect of MSCs on alleviating different types of Graft Versus Host Disease.  It has also been shown that the transplant of MSCs could help autoimmune diseases (El-Badri, 2004).

Cancer
Recent studies indicate that the body’s own MSCs can prevent the worsening of cancer by stabilizing the tumor’s blood vessels and not allowing any sustenance to pass through to the tumor.  However, when new MSCs are introduced in a mid-level cancer, the cancer seems to worsen.  This could be due to the property of MSCs that produce new blood vessels, which can assist the tumor (Xian, 2006).  Also, an experiment was conducted demonstrating that the body’s own MSCs set up areas for cancer to find sustenance and support (Steeg, 2005).  Further research is warranted to determine the exact function MSCs have in cancer.

Gene Delivery System
MSCs also have the possibility to be used as a gene delivery system. For example, we have seen MSCs that are able to migrate towards sites of injury via specific protein systems (Son, 2006).

Currently, MSCs are being studied in local implantation for diseases, transplantations, use in gene therapy, and the use in tissue engineering regeneration.  We have seen many positive results, but there is also the possibility for serious complications resulting in multiple organ failure.  This is because MSCs are closely linked to hematopoietic regulation and bone marrow support (Angelopoulou, 2003, Muguruma, 2006).  There is the possibility that scientists can cause more harm than good by altering our body’s MSCs.

There are several ongoing trials involving the use of MSCs as therapies. Areas of study include bone formation disease, heart failure, Crohn’s Disease, post-menisectomy treatment, regeneration of periodontal tissue, Graft Versus Host Disease, cancer, and multiple sclerosis (Horwitz, 2002).

Many scientists believe that MSCs will be involved in useful therapies in the future.   However, until we can study and control the affect of MSCs on the hematopoietic system and our ability to control MSC differentiation, the failure of MSC treatments might always be a possibility.

REFERENCES

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Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ (1998) Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats—similarities to astrocyte grafts.  Proc Natl Acad Sci U S A 95:3908-13.

Bianco P, Riminucci M, Gronthos S, Robey PG (2001) Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19:180-92.

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El-Badri NS, Maheshwari A, Sanberg PR (2004) Mesenchymal stem cells in autoimmune disease. Stem Cells Dev 13:463-72.

Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F (1998) Muscle regeneration by bone marrow-derived myogenic progenitors. Science 279: 1528-30.

Horwitz EM, Gordon PL, Koo WK, Marx JC, Neel MD, McNall RY, Muul L, Hofmann T (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci U S A 99:8932-7.

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Muguruma Y, Yahata T, Miyatake H, Sato T, Uno T, Itoh J, Kato S, Ito M, Hotta T, Ando K (2006) Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment. Blood 107: 1878-87.

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Potian J, Aviv H, Ponzio N, Harrison J, Rameshwar P (2003) Veto-like activity of mesenchymal stem cells: functional discrimination between cellular responses to alloantigens and recall antigens. J Immunol 171:3426-34.

Quirici N, Soligo D, Bossolasco P, Servida F, Lumini C, Deliliers GL (2002) Isolation of bone marrow mesenchymal stem cells by anti-nerve growth factor receptor antibodies.  Exp Hematol 30:783-91.

Son BR, Marquez-Curtis LA, Kucia M, Wysoczynski M, Turner AR, Ratajczak J, Ratajczak MZ, Janowska-Wieczorek A (2006) Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 24:1254-64.

Steeg PS (2005) Cancer biology: emissaries set up new sites.  Nature 438:750-1.

Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E, Giunti D, Ceravolo A, Cazzanti F, Frassoni F, Mancardi G, Uccelli A (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106(5): 1755-61.

Online Encyclopedia Entry for Julius Cohnheim: http://www.jewishencyclopedia.com/ view_friendly.jsp?artid=660&letter=C

Acknowledgements

This review was prepared by the following graduate students, Stem Cell Biology (Fall 2006), Graduate School of Biomedical Sciences, University of Medicine and Dentistry of New Jersey:

Tara Gooen, Joel Schneider, and James Sturzione (in alphabetical order)

Teaching Assistant: Kathy Trzaska