Clinical uses of mesenchymal stem cells

In the research process of expanding the therapeutic uses of mesenchymal stem cells, they are grown in laboratories or grown using medication to stimulate new cell growth within the human body. In mesenchymal stem cell therapy, most of the cells are extracted from the adult patient's bone marrow [2][3] Mesenchymal stem cells can be obtained via a procedure called bone marrow aspiration. A needle is inserted into the back of the patients hip bone and cells are removed to be grown under controlled in vitro conditions in a lab. Over a course of two or three weeks, the cells will multiply and differentiate into specialized cells. The number of fully differentiated cells and their phenotype can be influenced in three ways. The first one is by varying the initial seed density in the culture medium. The second is by changing the conditions of the medium. The third is by the addition of additives such as proteins or growth hormones to the culture medium to promote growth. The mature cells are then harvested and injected back into the patient through local delivery or systemic infusion.

Isolation of mesenchymal stem cells from the bone marrow requires an invasive procedure. Mesenchymal stem cells can also be isolated from birth-associated tissues such as the umbilical cord without the need for an invasive surgical procedure. Differences in isolation efficiency are attributed to the availability, condition, and age of the donor tissue. An issue related to culturing mesenchymal stem cells is the insufficient number of cells that can be produced.[1][3] During long-term culture, mesenchymal stem cells age, lose their ability to differentiate, and have a higher chance to undergo malignant transformation.[4][5]

A vast amount research has been conducted in recent years for the use of mesenchymal stem cells to treat multiple sclerosis.[17][18] This form of treatment for the disease has been tested in many studies of experimental allergic encephalomyelitis, the animal model of multiple sclerosis, and several published and on-going phase I and phase II human trials.[8][6][9][12]

Current treatments are unable to prevent the accumulation of irreversible damage to the central nervous system.[11] Patients with multiple sclerosis experience two major forms of damage, one from on-going autoimmune induced processes and the other to natural pair mechanisms.[6] Therefore, an ideal treatment must possess both immunomodulating properties to control irregular autoimmune responses and regenerative properties to stimulate natural repair mechanisms that can replace damaged cells.[8][6]

The exact therapeutic mechanisms of mesenchymal stem cells in the treatment of multiple sclerosis are still very much up to debate among stem cell researchers.[8][6][9] Some of the suggested mechanisms are immunomodulation, neuroprotection, and neuroregeneration.[6]

• Immunomodulation

Mesenchymal stem cells can induce the release of bioactive agents such as cytokines that can inhibit autoimmune responses.[8][6] In patients with multiple sclerosis, autoreactive lymphocytes such as T and B cells cause damage to the central nervous system 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.[11] By suppressing the unregulated proliferation of T and B cells, mesenchymal stem cells can potentially minimize and control on-going damage to the central nervous system.[8][9][11]

Mesenchymal stem cells can also stimulate the maturation of antigen presenting cells.[6][9] Antigen presenting cells trigger the immune system to produce antibodies that can destroy potentially harmful agents.[6] This property allows mesenchymal stem cells to actively contribute to neutralizing harmful autoreactive T and B cells.[8]

• Neuroprotection

Mesenchymal stem cells can promote neuroprotection in the central nervous systems which may prevent the progression of chronic disability.[11] The mechanisms include inhibiting apoptosis of healthy cells and preventing gliosis, the formation of a glial scar.[6][11] They can also stimulate local progenitor cells to produce replacement cells for rebuilding the myelin sheath.[6]

• Neuroregeneration

The regenerative abilities of the central nervous system are greatly decreased in adults, impairing its ability to regenerate axons following injury.[11] In addition to this natural limitation, patients with multiple sclerosis exhibit an even greater decrease in neuroregeneration along with enhanced neurodegeneration.[8][11][17][18] They experience a significant decrease in the number of neural stem cells which produce progenitor cells necessary for normal maintenance and function.[6][9] Decreases in the neural stem cells results in severe damage to the ability of the central nervous system to repair itself.[9] This process results in the amplified neurodegeneration exhibited in patients with multiple sclerosis.[6][9]

Mesenchymal stem cells have the ability to stimulate neuroregeneration by 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.[11][19] Regeneration and repair of damaged axons has been shown to occur naturally and spontaneously in the central nervous system. This shows that it is an environment capable of unassisted, natural healing.[19] Mesenchymal stem cells contribute to this regenerative environment by releasing bioactive agents that inhibit apoptosis and thus create an ideal regenerative environment.[6]

Mesenchymal stem cells are able to alleviate heart fiber injury and prevent cardiac muscle cell death in mouse models of myocardial infarction, or heart attack, and prevent its further development.[20][21][22] They can migrate to areas of inflammation and decrease infarction and improve cardiac function.

Mesenchymal stem cells have the potential to treat brain strokes as well. They can secrete factors that stimulate the function of brain cells, leading to neuron formation, blood vessel formation, and improved synaptic plasticity. They can also differentiate into neurons and neural cells to replace damaged cells. Behavioral tests performed in mouse models demonstrated a return to normal brain function after treatment with mesenchymal stem cells.[23][24]

Mesenchymal stem cells can also regenerate and repair damaged liver cells. In mouse models of liver fibrosis, mesenchymal stem cells delivered to the liver were shown to improve liver function by reducing inflammation and necrosis and inducing hepatocyte regeneration.[25][26][27]