Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jul
25
2011

Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) are a type of multipotent stem cell, meaning that they can give rise to many but not all types of cells in the body. MSCs secrete substances, including cytokines and growth factors, that are essential to cell growth and help repair damaged tissue. Researchers are still exploring the functions of human MSCs in the body, but current knowledge about the stem cells suggests that they play an important role in cell repair, acting as a sort of “cellular paramedic.”

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Mesenchymal Stem Cells: The Cellular Paramedic^

MSCs can be thought of as “cellular paramedics,” helping to restore damaged cells and tissue. As mentioned before, MSCs are able to secrete substances like cytokines and growth factors that can promote tissue repair. MSCs have even been shown to transfer products as large as mitochondria to damaged cells that need help. Specifically, MSCs stimulate angiogenesis, the process of new blood vessel formation, which has been linked to neurogenesis, the process by which new nerve cells are produced. The factors secreted by MSCs also reduce the harmful effects of oxidative damage and apoptosis.

When researchers discovered the “paramedic” quality of MSCs, they conducted several experiments to see how MSCs could potentially be used to help treat human diseases. In one experiment, MSCs obtained from humans were injected into mice that had some type of tissue damage and did not have a functional immune system. The MSCs were labeled so that scientists could track where they migrated after being injected into the mice. The researchers observed that the cells migrated throughout the damaged tissues apparently evenly and continued to be present in the tissue for a substantial period of time. The continued presence of MSCs is important to therapeutic development because it indicates that potential positive long-term effects of a treatment might be capable of persisting.

In additional experiments, scientists found that MSCs function differently in chronic disease models than in more temporary conditions like injury and trauma. In mouse models of acute injury, injected MSCs responded by helping to repair the tissue but were not present in the tissue for a substantial period of time, as they were in mouse models of chronic disease. For more information on mouse models, click here. When the experiment was repeated in injured mice without functional immune systems, the MSCs were again only temporarily present in the tissue. This suggests that temporary presence of MSCs is not a result of the host immune system. It is important to establish what types of environment foster the sustained presence of MSCs in the tissue so that clinicians can increase the effectiveness of future treatments using MSCs.

Research Using Mesenchymal Stem Cells^

The unique ability of MSCs to secrete their own growth factors enables scientists to culture them in a laboratory with relatively little maintenance. Furthermore, MSCs multiply rapidly in cell cultures. As a result, compared to other cells, it is easier to grow many MSCs after obtaining a limited number of the cells from a patient. Cells that are grown in vitro often develop different characteristics or stop multiplying after a period of time. However, MSCs have been found to maintain their characteristics and the ability to multiply even after many cycles of replication. Most other cells require expensive cytokines and growth factors to grow in vitro, so the low maintenance of MSCs increases their appeal as a source of stem cells to investigate potential treatments.

In the body, MSCs are found in the bone marrow, umbilical cord tissue, and fat pads.  MSCs are relatively rare in the bone marrow, comprising only 1 out of every 10,000 cells. On the other hand, umbilical cord blood and fat are rich sources of MSCs. Human MSCs can be harvested with minimal patient discomfort by tapping into an individual’s marrow space or fat pads.

Unlike most other cells, MSCs can be transferred between organisms with little immune rejection, in which the immune system of the organism receiving the transplant attacks the foreign tissue being transplanted. Scientists have found that MSCs suppress the immune system and reduce inflammation, making them good candidates for transplantation or injection into a host because they can avoid rejection by the host’s immune system.

The ease with which MSCs can be obtained, cultured, and transferred into a host without immune rejection is one reason why researchers are hopeful that MSCs may offer a promising way for scientists to develop treatments for neurodegeneration.

MSCs and the Brain^

In the brain, MSCs can help repair neurodegeneration by providing neurotrophic factors, proteins in the nervous system that promote the growth of nerve cells. For example, detailed experiments have shown that human MSCs express the neurotrophic factor BDNF (brain-derived neurotrophic factor) but do not express certain types of neurotrophins. You can read more about BDNF by visiting the HOPES article here. Interestingly, MSCs still exhibited their “cellular paramedic” effects when BDNF activity is blocked by an antibody, suggesting that MSCs secrete factors other than BDNF that help with cellular growth in the brain.  The effects of these factors allow nerve cells to carry out several processes that support survival: axon extension, growth, and cell attachment. In essence, MSCs change the tissue environment to enhance cell growth and regeneration in the brain.

Experiments done on mice with nerve cell injury have shown that MSCs injected into the brain promote recovery by secreting neurotrophic factors that facilitate nerve cell survival and regeneration. More relevant to HD are animal experiments showing that MSCs have the potential to repair striatal degeneration.

Bantubungi et al conducted experiments using rat MSCs to help treat rat models of HD with parts of their striatum removed. The research showed that MSCs proliferated more rapidly in the rat brains with striatal lesions than in healthy rat brains, suggesting that MSCs selectively respond to areas needing repair.  Furthermore, the scientists identified a protein called stem cell factor that encouraged proliferation and directed migration of the MSCs to damaged tissue. Stem cell factor is a naturally occurring protein that plays an important role in communication between cells. The experiment by the scientists suggests that MSCs do in fact play an important role in the brain and have potential to become a cellular therapy for neural repair.

Amin et al. conducted an experiment in which rat models of Huntington’s disease with damage to one side of the brain responded positively to MSC implantation into the brain. Specifically, damage within the striatum, the region of the brain drastically affected in HD, was significantly reduced in rats that received MSC implantations.

It is important to note that although MSCs promote cell growth and repair in the brain, scientists have not yet confirmed that MSCs can become mature nerve cells with the ability to signal, or communicate with, other nerve cells. Other types of stem cells, such as neural stem cells have been found to generate mature nerve cells. MSCs may not be able to become mature nerve cells themselves.

Genetically Engineered MSCs^

In addition to exploiting the natural ability of MSCs to help repair damaged nerve cells, scientists have found ways to genetically engineer MSCs to enhance their reparative properties in the brain. Scientists can introduce genes into MSCs that cause them to produce a greater quantity of factors such as cytokines and neurotrophins. Even after genetically engineered MSCs are allowed to multiply through several generations, they retain these genetic characteristics that boost production of helpful factors.  Furthermore, MSCs have proven to be robust cells: genetic engineering does not hinder the cells’ ability to multiply or grow. It is important however to continue these types of studies to ensure there are no unintended side effects of enhanced neutrophin and cytokine productions in MSCs or other cells and tissues in the body.

An experiment conducted by Dey et al. showed that mouse models of HD responded positively to treatment by MSCs. When the MSCs were genetically engineered to produce greater quantities of BDNF, the delay in disease progression was even more drastic in the mice.

The potential to genetically engineer MSCs to deliver factors such as BDNF is important because directly injecting some of these factors is not effective. Transplanted MSCs, as indicated in the studies mentioned above, have been shown to disperse throughout damaged tissue for a sustained period of time. The characteristics of the compounds themselves often prevent them from having a sustained physiological effect on their own. Therefore, the genetically engineered MSCs serve as a vehicle to enable effective delivery of helpful factors into the brain.

Another exciting possibility is to have MSCs themselves become vehicles for delivering genetic material that can help with diseases like HD. Dr. Jan Nolta’s research group at University of California Davis, for example, hopes to have MSCs deliver molecules for RNA interference, a type of gene therapy, into the cells of HD patients. You can read more about RNAi in the HOPES article here. This area of research is still in its preliminary stages and may take several years to obtain approval from government agencies such as the Food and Drug Administration (FDA). Nevertheless, it holds promise as a potential future treatment for HD.

A Potential Treatment for HD Using MSCs^

Future cellular therapies using MSCs would involve delivering MSCs into the brain, which has been approached in a number of different ways. Scientists have proposed delivering MSCs through an injection directly into the brain, an injection into the space surrounding the spinal cord, or a route through the nose (e.g. a nasal spray).

Although clinical trials using MSCs in humans have not yet been approved in the United States, one human cellular therapy trial has been conducted in France. In the trial, neural stem cells rather than MSCs were used. Five patients with HD received transplants from human fetal neural stem cells. After two years, three out of the five patients demonstrated motor and cognitive improvements. While this experiment provides hopeful evidence that stem cell therapies may provide a treatment for HD, the results should be interpreted with caution. First, two of the patients did not show significant improvements. Second, as noted before, neural stem cells and MSCs have different characteristics. Therefore, the results from this experiment do not indicate whether MSCs would provide an effective treatment. Finally, after four to six years, the patients showed clinical decline once again, suggesting that additional research is required before an effective long-term treatment is developed.

In addition to showing that stem cells are in fact an effective treatment for HD, researchers must also show that implanting MSCs into the brain is a safe procedure before treatments can continue to be developed. One of the main concerns with MSCs is that they could cause abnormal cell growth. Abnormal growth could result in extra bone or tumor formation. In particular, MSCs have been found to migrate to areas in the body that contain tumors. This could be dangerous if the MSCs excrete factors that encourage angiogenesis, cell growth, and cell proliferation within the tumor. For safety reasons, proposed clinical trials for cellular therapies exclude anyone who has had a brain tumor or other cancer within the past 5 years. Before treatment, an MRI will be administered to ensure the absence of any brain tumors.

Extensive biological safety trials have been conducted with MSCs by Dr. Gerhard Bauer and Dr. Jan Nolta at University of California at Davis. They have performed numerous experiments over the past decade on different animal models including mice, rats, and primates, to test if MSCs can be safely injected or grafted without tumorous growths.  Additionally, a successful clinical trial in France with five HD patients suggests that transplantation of stem cells into the brain can be done without negative health consequences. However, more evidence for the biological safety of injecting MSCs into the brain is needed to meet the rigorous safety standards of the FDA in the United States

MSCs have potential to be a safe and effective therapy for HD. While there is promising evidence from animal research that MSCs can slow neurodegeneration, specifically in the striatum, there are still many aspects of the potential therapy that require additional experimentation.

Further reading:^

1.     Aggarwal, S. and M. F. Pittenger (2005). “Human mesenchymal stem cells modulate allogeneic immune cell responses.” Blood 105(4): 1815-1822.

A technical paper that discusses how MSCs interact with the immune system.

2.     Aizman, I., C. C. Tate, et al. (2009). “Extracellular matrix produced by bone marrow stromal cells and by their derivative, SB623 cells, supports neural cell growth.” J Neurosci Res 87(14): 3198-3206.

A technical paper that talks about the various compounds secreted by MSCs

3.     Amin, E. M., B. A. Reza, et al. (2008). “Microanatomical evidences for potential of mesenchymal stem cells in amelioration of striatal degeneration.” Neurol Res 30(10): 1086-1090.

This paper discusses how MSCs might help counter nerve cell damage in the striatum, and is difficult

4.     Bachoud-Levi, A. C., V. Gaura, et al. (2006). “Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study.” Lancet Neurol 5(4): 303-309.

This is the study in which human fetal neural stem cells were transplanted into HD patients

5.     Bantubungi, K., D. Blum, et al. (2008). “Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington’s disease.” Mol Cell Neurosci 37(3): 454-470.

A technical paper that discusses transplantation of MSCs in rats

6.     Crigler, L., R. C. Robey, et al. (2006). “Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis.”

This paper discusses some of the compounds that MSCs secrete that play a role in nerve cell health, and is quite difficult

7.     Danielyan, L., R. Schafer, et al. (2009). “Intranasal delivery of cells to the brain.” Eur J Cell Biol 88(6): 315-324.

This paper discusses one of the several ways MSCs might be delivered through the brain.

8.     Dey, N. D., M. C. Bombard, et al. (2010). “Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease.” Behav Brain Res 214(2): 193-200.

This technical paper discusses how MSCs helped behavior problems in a mouse model of HD.

9.     Joyce, N., G. Annett, et al. (2010). “Mesenchymal stem cells for the treatment of neurodegenerative disease.” Regen Med 5(6): 933-946.

This paper discusses potential applications of MSCs in medicine, and is of medium difficulty

10.  Meyerrose, T. E., M. Roberts, et al. (2008). “Lentiviral-transduced human mesenchymal stem cells persistently express therapeutic levels of enzyme in a xenotransplantation model of human disease.” Stem Cells 26(7): 1713-1722.

This technical paper discusses how MSCs migrate through the nervous system when introduced into a mouse’s brain

11.  Spees, J. L., S. D. Olson, et al. (2006). “Mitochondrial transfer between cells can rescue aerobic respiration.” Proc Natl Acad Sci U S A 103(5): 1283-1288.

This technical paper describes how transfer of mitochondria between cells can help the cell that receives the mitochonfrion

12.  Wineman, J., K. Moore, et al. (1996). “Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells.” Blood 87(10): 4082-4090.

This technical paper discusses the conditions needed to grow MSCs

T. Wang, 7-25-11