Mesenchymal Stem Cell Therapy

Literature Review: Mesenchymal Stem Cell Therapy.

Mesenchymal stem cells are multipotent cells that can differentiate to become a range of different mesenchymal tissues. Stem cells of mesenchymal origin are thought to be the most promising type of stem cell to be used in medical applications. Mesenchymal stem cells reside primarily in the bone marrow and adipose tissue and can be isolated from adult bone marrow samples with comparative ease. Mesenchymal stem cells are mainly extracted from the iliac crest of adults; however, mesenchymal stem cells can also be found and extracted from foetal liver and cord blood. MSCs have a wide distribution throughout the human body; they have been isolated from a variety of tissue origins, examples include adipose tissue, skeletal muscle, dermis, lung and dental pulp. Mesenchymal stem cells can also be found at very low concentrations in the peripheral blood of an adult human (Dazzi, Horwood 2007).

Mesenchymal stem cells provide a good prospective for therapies to treat a variety of diseases and conditions, due to the capacity of MSCs to differentiate into a range of tissues of mesenchymal origin. It is thought that mesenchymal stem cells will be of therapeutic use in regenerative medicine and could additionally be used for treating graft-verses-host disease and autoimmune diseases (Chen, Shao et al. 2008).

Current research into the potential applications of mesenchymal stem cells and their possible therapeutic properties include therapies to aid and accelerate the recovery of the heart after myocardial infraction and treatments for autoimmune diseases (Chen, Shao et al. 2008). Mesenchymal stem cells can take on a tissue repair mechanism as the cells have the ability to differentiate into specific cell types, under the right circumstances in an environment, to replace the injured cells. It has also been reported that MSCs could be able to trans-differentiate into cells of neuroectoderm and endoderm cell lineages under specific in vitro environments (Jiang, Jahagirdar et al. 2002).

The concept of using mesenchymal stem cells for a therapeutic purpose is still undergoing rigorous test and studies for research purposes on animals such as mice, pigs and primates. Some more advanced clinical trials on humans for certain diseases are being carried out in patients with no other current treatment options. However there are still some concerns about the potential risks and side effects that could be associated with this type of therapy. Some studies have found evidence that mesenchymal stem cells could encourage the progression of tumour attachment and growth (Ramasamy, Lam et al. 2007).

In healthy animals, the preferred homing destination for MSCs that have been injected intravenously is the bone marrow (Devine, Bartholomew et al. 2001). However, if an area of inflammation was present in the animal, the intravenously injected MSCs would preferentially migrate to the area of inflammation (Saito, Kuang et al. 2002). The mechanisms of this response is not totally understood, however, it is likely to be due to the increase in inflammatory chemokine concentration present at the site of inflammation consequently causing the MSCs to migrate to the inflamed site(Brooke, Cook et al. 2007). If tissues become damaged chemokines are released at this inflamed site; MSCs express the receptors for several chemokines (Fox, Chamberlain et al. 2007) therefore this offers a likely explanation for why MSCs will tend to migrate to inflamed tissues.

Mesenchymal stem calls inhabit the connective tissues of the majority of organs. Mesenchymal stem cells possess the innate ability to migrate to sights of injured cells or tissues, areas of inflammation and tumours.

Myocardial infarction occurs due to lack of blood supply to the heart muscle, subsequently resulting in myocardial cell death. A larger myocardial infarction will cause more widespread damage to the myocardium, leading to necrosis and formation of scar tissue. Overall heart function is decreased and this results in a worse prognosis for the patient. MSCs could be used to trans-differentiate into myocardium and therefore help to regain lost heart function. In a study using animal mouse models, injection of MSCs into a recently infracted heart resulted in almost 70% of the infracted tissue portion being occupied by newly formed myocardium within 9 days of the myocardial infarction (Orlic, Kajstura et al. 2003) . Studies such as this have identified MSCs as candidates for cell-based tissue regeneration therapy. In addition to this another study has demonstrated that in healthy rats that received intravenous injection of LacZ labelled murine MSCs, these MSCs localised in the bone marrow of the rats. However when this same procedure was undertaken using rats that had experienced myocardial infarction, the LacZ labelled MSCs were found to be localised in the infracted portion of the heart (Saito, Kuang et al. 2002). This observation further supports the finding of some researchers that mesenchymal stem cells will migrate to areas of inflammation and tissue damage. Both of these sets of findings further go on to prove that intravenous MSC therapy improves ventricular functioning and recovery of infracted myocardium. However there is some controversy concerning these findings; some research has suggested that the improvement in ventricular functioning is due to cell fusion as opposed to cell differentiation into new specialised myocardial cells.

The use of mesenchymal stem cells as a therapy for stroke patients has been explored by some researchers. Various studies have found that if MSCs are intravenously injected into a stroke patient they will migrate to the inflamed areas of the CNS, and differentiate into cells expressing neural markers and restore damaged neural cells. It was observed that the direct transplantation of MSCs into the brains of rats was safe and leads to the recovery of the rat's symptoms associated with stroke damage (Li, Chen et al. 2005). Studies such as this support the notion that MSCs are practical candidates for the treatment of stroke to reduce the symptoms resulting from tissue damage of the CNS. The mechanisms by which this functional recovery is induced or carried out is indefinite; it is a possibility that the MSCs combine with the existing tissue of the CNS and replace those cells that are damaged and reform circuits for transmission of neural signalling (Chen, Li et al. 2001) and therefore restores neural function.

Some recent research has indicated that mesenchymal stem cells could be used as a treatment or potential cure for diabetes mellitus. Cardiac infusion of human MSCs into mice with induced hypoglycaemia resulted in a lower blood glucose concentration being found in the treated diabetic mice compared to the untreated control diabetic mice. However there was no detection of human insulin. The absence of human insulin and an increased level of mouse insulin found in the treated diabetic mice compared to untreated controls indicated that the human MSCs increased the number of mouse islets of langerhans and mouse insulin producing cells. Few of the human MSCs differentiated into human insulin secreting cells (Lee, Seo et al. 2006) implying that the human MSCs induced repair of the mouse islets.

Mesenchymal stem cells' therapeutic uses are also being investigated for liver repair, restoration and tissue engineering. When MSCs are incubated with specific growth factors such as hepatocyte growth factor (HGF) the MSCs differentiate to take on a hepatic cell lineage (Fiegel, Lange et al. 2006).

MSCs have immunosuppressive properties; therefore they also offer a possible therapy to be used in conjunction with the organ transplantation. MSCs could be used as a preventative method for acute organ rejection that is often an issue for clinical patients. Usually strong immunosuppressive drugs are used to prevent transplant rejection; these have serious associated risks including susceptibility to rare and serious infections. Alternatively using MSCs presents an immunosuppressive therapy coupled with the ability of tissue repair of ischaemic damage. There have been conflicting results from investigative studies for this potential use of MSCs and therefore further research is required to accurately assess the effectiveness of the use of MSCs in organ transplantation (Brooke, Cook et al. 2007).

Several studies have shown that there is a possibility that MSCs could promote the development of tumours. The exact mechanism by which this is carried out is not fully understood; it is thought that the MSCs could be providing a niche for cancer stem cells to develop and proliferate. Alternatively the presence of MSCs in tissues could be impairing immune scrutiny or this could be an example of the graft versus leukaemia effect (Dazzi, Horwood 2007). On the other hand some studies have found that MSCs inhibit tumour growth in murine and rat models. In vitro there is evidence that MSCs display powerful antiproliferative properties in different tumour cell lines; contradictory to this when studied in vivo MSCs facilitate tumour engraftment and growth (Ramasamy, Lam et al. 2007). Due to uncertainty concerning this possible side effect of MSC therapy, therapies that use MSCs as a mechanism for regeneration or repair of tissues are being used only in situations where the patient has exhausted all other treatment options without any success.

The immunomodulating effect of MSCs could be used therapeutically in the treatment of autoimmune diseases such as multiple sclerosis or rheumatoid arthritis (Chen, Shao et al. 2008), as current treatment options for these diseases are currently limited and aren't advantageous for all patients.

In conclusion it is evident that mesenchymal stem cells hold a great potential for therapies or even cures for a wide range of diseases, a few of which have been touched upon in this review. There have been many studies, mostly in animal models, providing conflicting evidence concerning the therapeutic use of mesenchymal stem cells. As the mechanisms by which MSCs work and undergo differentiation, into specific cell types leading to cell regeneration, are currently not understood fully more research and extensive studies will be required to entirely understand how mesenchymal stem cell therapy works and how it can be best manipulated in order to see the greatest effects from this type of therapy. Techniques used to isolate MSCs differ from study to study, and as there is no strict guideline for the specific characterisation of a single mesenchymal stem cell it is increasingly difficult to compare and evaluate the results of different researchers. Many of the findings from recent studies have either been conducted in animal models or on human MSCs in vitro, very few applications have been clinically tested in vivo. As the mechanisms by which MSCs actually work is unknown clinical trials using MSCs will have to be handled with great care requiring extensive monitoring procedures as they may behave differently to what is being observed and what would be expected in animals or in laboratories.

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JIANG, Y. , JAHAGIRDAR, B.N. , REINHARDT, R.L. , SCHWARTZ, R.E. , KEENE, C.D. , ORTIZ-GONZALEZ, X.R. , REYES, M. , LENVIK, T. , LUND, T. , BLACKSTAD, M. , DU, J. , ALDRICH, S. , LISBERG, A. , LOW, W.C. , LARGAESPADA, D.A. and VERFAILLIE, C.M. , 2002. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 418(6893), pp. 41-49.

LEE, R.H. , SEO, M.J. , REGER, R.L. , SPEES, J.L. , PULIN, A.A. , OLSON, S.D. and PROCKOP, D.J. , 2006. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proceedings of the National Academy of Sciences of the United States of America, 103(46), pp. 17438-17443.

LI, Y. , CHEN, J. , ZHANG, C.L. , WANG, L. , LU, D. , KATAKOWSKI, M. , GAO, Q. , SHEN, L.H. , ZHANG, J. , LU, M. and CHOPP, M. , 2005. Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia, 49(3), pp. 407-417.

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RAMASAMY, R. , LAM, E.W. , SOEIRO, I. , TISATO, V. , BONNET, D. and DAZZI, F. , 2007. Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 21(2), pp. 304-310.

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