Clinical uses of mesenchymal stem cells

Adult mesenchymal stem cells (MSCs) are being used by researchers in the fields of regenerative medicine and tissue engineering, to artificially reconstruct human tissue which has been previously damaged. Mesenchymal stem cells have the capacity to become any type of fully developed cell, which can contribute to replacing muscle tissues or internal organs. To help discover the therapeutic uses of these stem cells they are grown in laboratories or by using medication to stimulate new cell growth within the human body.^[1][2][3] In MSC therapy the cells are extracted from the adult patient’s bone marrow via a procedure called bone marrow aspiration. This usually involves inserting a needle into the back of the patients hip bone and removing the sample from there. These cells are then grown under controlled in vitro conditions in a lab, so that they can multiply and same time mature( also referred to as differentiated. This process may take two to three weeks.^[1] The kind of mature, fully differentiated cell phenotype and the number of those cells created though this can be influenced in three ways. Firstly by varying the initial seed density in the culture medium, secondly through changing the conditions of the medium during expansion, and lastly through the addition of additives such as proteins or growth hormones to the culture medium.^[4]. They are then harvested and put back into the patient through local delivery or systemic infusion.^[1][2][4]

Therapeutic properties

See also: Mesenchymal stem cell

MSCs possess many properties that are ideal for the treatment of inflammatory and degenerative diseases.^[2][3] They can differentiate into many cell types including bone, fat, and muscle which allow them to treat a large range of disorders.^[1][4] They possess natural abilities to detect changes in their environment, such as inflammation. They can then induce the release of bioactive agents and the formation of progenitor cells in response to these changes.^[4] MSCs have also been shown to travel to sites of inflammation far from the injection site.^[3][5][6]

MSCs can be easily extracted through well-established procedures such as bone marrow aspiration.^[3] Also, transplanted MSCs do not pose any potential for rejection by the patient as they are derived from the patient’s own tissue.^[2]

Advantages over embryonic stem cells

See also: Stem cell treatments

Several different forms of stem cells have been identified and studied in the field of regenerative medicine. One of the most extensively studied stem cell types are embryonic stem cells (ESCs). ESCs possess many of the same therapeutic properties as MSCs, including the ability to self-regenerate and differentiate into a number of cell lineages.^[1] Their therapeutic abilities have been demonstrated in a number of studies of autoimmunity and neurodegeneration in animal models.^[1][3][5][7]

However, their therapeutic potential has been largely limited by several key factors.^[3] Injected ESCs have been shown to increase the risk for tumor formation in the host patient.^[1][3][7] Also, the host’s immune system may reject injected ESCs and thus eliminate their therapeutic effects1.^[3] Finally, research has been largely limited due to the ethical issues that surround their controversial procurement from fertilized embryos.^[1][7]

Treated disorders

MSCs have been used to treat a variety of disorders including cardiovascular diseases, spinal cord injury, bone and cartilage repair, and autoimmune diseases.^[4]

Treatment for multiple sclerosis

A vast amount research has been conducted in recent years for the use of MSCs to treat multiple sclerosis (MS).^[8][9] This form of treatment for the disease has been tested in many studies of experimental allergic encephalomyelitis, the animal model of MS, and several published and on-going phase I and phase II human trials.^[1][2][4][7]

Treatment requirements

See also: Treatment of multiple sclerosis

Current treatments are unable to prevent the accumulation of irreversible damage to the central nervous system (CNS).^[6] MS patients experience two major forms of damage, damage resulting from on-going autoimmune induced processes and damage to natural pair mechanisms.^[2] Therefore, an ideal treatment must possess both immunomodulating properties to control irregular autoimmune responses to prevent further damage and regenerative properties to stimulate natural repair mechanisms and replace damaged cells.^[1][2]

Therapeutic mechanisms

The exact therapeutic mechanisms of MSCs in the treatment of MS are still very much up to debate among stem cell researchers.^[1][2][4] Some of the suggested mechanisms are immunomodulation, neuroprotection, and neuroregeneration.^[2]

• Immunomodulation

MSCs exhibit immunmodulatory properties through the release of bioactive agents such as cytokines that can inhibit autoimmune responses.^[1][2] In patients with MS, autoreactive lymphocytes such as T and B cells cause damage to the CNS by attacking myelin proteins. Myelin proteins make up the myelin sheath that functions in protecting nerve axons, maintaining structural integrity, and enabling the efficient transmission of nerve impulses.^[6] By suppressing the unregulated proliferation of T and B cells, MSCs can potentially minimize and control on-going damage to the CNS.^[1][4][6]

MSCs can also produce an immunomodulating effect by stimulating the maturation of antigen presenting cells.^[2][4] Antigen presenting cells trigger the immune system to produce antibodies that can destroy potentially harmful material.^[2] This property allows MSCs to actively contribute to neutralizing harmful autoreactive by-products of MS.^[1]

• Neuroprotection

MSCs can promote neuroprotection in the CNS of patients with MS which may prevent the progression of the disease to chronic disability.^[6] MSCs contribute to neuroprotection through several different mechanisms. These mechanisms include inhibiting apoptosis which will prevent the death of healthy cells and prevent gliosis which will prevent the formation of a glial scar.^[2][6] They can also stimulate local progenitor cells to produce replacement cells that can assist in rebuilding the myelin sheath.^[2]

• Neuroregeneration

The CNS’s regenerative abilities are greatly decreased in adults, impairing its ability to regenerate axons following injury.^[6] In addition to this natural limitation, MS patients exhibit even greater decreases in neuroregeneration coinciding with increases in neurodegeneration.^[1][6][8][9] In particular, MS patients experience a significant decrease in the number of neural stem cells which are responsible for producing large numbers of progenitor cells that are necessary for normal maintenance and function.^[2][4] Decreases in the neural stem cells results in severe damage to the CNS’s ability to repair itself.^[4] This process results in the amplified neurodegeneration exhibited in MS patients.^[2][4]

MSCs have the ability to stimulate neuroregeneration by contributing to cell replacement through differentiating into neural stem cells in response to inflammation. The neural stem cells can then promote the repair of damaged axons and create replacement cells for the damaged tissue.^[6][10]

Regeneration and repair of damaged axons has been shown to occur naturally and spontaneously in the CNS. This shows that it is an environment capable of unassisted, natural healing. naturally possesses an environment that is susceptible to regeneration.^[10] MSCs contribute to this regenerative environment by releasing bioactive agents that inhibit apoptosis and thus create an ideal regenerative environment.^[2]

References

1. ^ ^{a b c d e f g h i j k l m n o} Karussis D, Kassis I, Kurkalli BG, Slavin S (February 2008). "Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells (MSCs): a proposed treatment for multiple sclerosis and other neuroimmunological/neurodegenerative diseases". J. Neurol. Sci. 265 (1-2): 131–5. doi:10.1016/j.jns.2007.05.005. PMID 17610906. 
2. ^ ^{a b c d e f g h i j k l m n o p q} Yamout B, Hourani R, Salti H, et al. (October 2010). "Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study". J. Neuroimmunol. 227 (1-2): 185–9. doi:10.1016/j.jneuroim.2010.07.013. PMID 20728948. 
3. ^ ^{a b c d e f g h} Mallam E, Kemp K, Wilkins A, Rice C, Scolding N (August 2010). "Characterization of in vitro expanded bone marrow-derived mesenchymal stem cells from patients with multiple sclerosis". Mult. Scler. 16 (8): 909–18. doi:10.1177/1352458510371959. PMID 20542920. 
4. ^ ^{a b c d e f g h i j k l} Caplan A. 2010. "Mesenchymal stem cells: the past, the present, the future". Cartilage. 1(1):6-9.
5. ^ ^{a b} Ooi YY, Ramasamy R, Rahmat Z, et al. (December 2010). "Bone marrow-derived mesenchymal stem cells modulate BV2 microglia responses to lipopolysaccharide". Int. Immunopharmacol. 10 (12): 1532–40. doi:10.1016/j.intimp.2010.09.001. PMID 20850581. 
6. ^ ^{a b c d e f g h i} Payne N, Siatskas C, Bernard CC (November 2008). "The promise of stem cell and regenerative therapies for multiple sclerosis". J. Autoimmun. 31 (3): 288–94. doi:10.1016/j.jaut.2008.04.002. PMID 18504116. 
7. ^ ^{a b c d} Yang J, Yan Y, Ciric B, et al. (October 2010). "Evaluation of bone marrow- and brain-derived neural stem cells in therapy of central nervous system autoimmunity". Am. J. Pathol. 177 (4): 1989–2001. doi:10.2353/ajpath.2010.091203. PMID 20724590. 
8. ^ ^{a b} Guo J, Li H, Yu C, et al. (2010). "Decreased neural stem/progenitor cell proliferation in mice with chronic/nonremitting experimental autoimmune encephalomyelitis". Neurosignals 18 (1): 1–8. doi:10.1159/000242424. PMID 19786810. 
9. ^ ^{a b} Capello E, Vuolo L, Gualandi F, et al. (October 2009). "Autologous haematopoietic stem-cell transplantation in multiple sclerosis: benefits and risks". Neurol. Sci. 30 Suppl 2: S175–7. doi:10.1007/s10072-009-0144-5. PMID 19882370. 
10. ^ ^{a b} Scolding N, Marks D, Rice C (February 2008). "Autologous mesenchymal bone marrow stem cells: practical considerations". J. Neurol. Sci. 265 (1-2): 111–5. doi:10.1016/j.jns.2007.08.009. PMID 17904159.