Originally Published in The Siegel Rare Neuroimmune Association Journal
Volume VI
March 2012

Dr. Michael Levy
Assistant Professor of Neurology
Transverse Myelitis Center
Johns Hopkins Medical Center

Stem cells offer the best hope of neurologic recovery in transverse myelitis, acute disseminated encephalomyelitis, neuromyelitis optica and optic neuritis.

Stem cells are defined as an immature cell that has the potential to develop into a mature, functioning cell.  In the developing embryo, for example, all cells are initially stem cells. As the embryo begins to grow tissues, those stem cells mature into functional cells that make organs like the liver, kidney and brain (Figure 1 – Mike Jones [CC-BY-SA-2.5], via Wikimedia Commons). There are many steps cells take in their development between the early embryonic stem cell stage and the final mature cell stage. At each point in their development, they become more and more specialized toward their fate. The goal of using stem cells for clinical benefit is to take advantage of their potential to grow into cells that are missing from the patient or need to be replaced.  In the case of transverse myelitis, the goal is to regenerate spinal cord cells that were lost due to inflammation.

The classic teaching in neurology is that once you destroy neurologic tissue from disease, infection or trauma, there is no regeneration. In this way, the spinal cord is very different from other organs such as the kidney, liver and bone marrow which have a remarkable capacity to regenerate. We now recognize that there is some recovery by endogenous mechanisms in the spinal cord. Endogenous regeneration refers to the ability of the patient’s own stem cells to migrate to the site of the damage and initiate repair. These stem cells originate deep in the brain and can travel down to the spinal cord when needed. But in the majority of spinal cord damage in humans, the stem cells that arrive mysteriously do not mediate repair and eventually die off. There is an effort to understand this potential repair mechanism and enhance it (see Biogen’s new drug in development: anti-Lingo antibody) and that is the subject of another review article.

There are other stem cell trials taking place in diseases related to transverse myelitis, but they do not focus on regeneration. Rather, these “stem cells” which come from the bone marrow, are used to modulate the immune system in patients who have recurrent inflammatory disease, such as multiple sclerosis, neuromyelitis optica, or recurrent transverse myelitis. The bone marrow contains two types of stem cells, those that will become immune cells and the rest are called mesenchymal stem cells.

Immune stem cells are being studied for their ability to reboot the immune system in patients with recurrent disease. The approach is similar to a bone marrow transplant in which a small number of the patient’s healthy immune stem cells are harvested and stored in the lab while chemotherapy drugs are used to wipe out the rest of the immune system. Then the healthy immune stem cells are replaced and the immune system reboots entirely from those healthy immune stem cells. This approach is not useful for patients who have monophasic, idiopathic transverse myelitis because those patients do not have an aberrant immune system; rather, those patients have a healthy immune system that made one devastating mistake in the past.

Mesenchymal stem cells also come from the bone marrow but do not become immune cells. In the body, they normally turn into fat cells, cartilage cells for joints, and bone cells. In the lab, we can turn mesenchymal stem cells into many more types of cells with the right combination of growth factors and hormones, including nerve cells. The potential for mesenchymal stem cells to become nerve cells prompted a rush of research into using them to regenerate the nervous system. Early studies showed that a single injection of mesenchymal stem cells in mouse models of multiple sclerosis ameliorates the disease. Later studies have confirmed those results, but concluded that the effect of the mesenchymal stem cells was on the immune system and not due to regeneration of nerve tissue. Although not completely understood, it appears that mesenchymal stem cells harvested from the bone marrow of a patient then injected back into the same patient’s bloodstream have a calming effect on the immune system. Because the cells are coming from the patient’s own bone marrow, this procedure is very safe because the stem cells have the same genetic identity and still recognize their new environment as self. There are essentially no long term complications from this procedure although bone marrow harvesting can be a little painful. Nevertheless, two groups are moving forward with mesenchymal stem cell transplantation studies in the United States. This follows work in other countries where mesenchymal transplantation in multiple sclerosis has shown some benefit in modulating the immune system. It should be noted that mesenchymal stem cells in animals and humans have never been shown to become neural cells. Even when injected into the spinal fluid of patients, they only appear to interact with immune cells in the brain and spinal cord and not develop into neural cells. Similar to other bone marrow stem cell approaches, there is no potential for regeneration of the spinal cord in mesenchymal stem cell transplantation.

A new type of cell from the bone marrow has recently been identified and named Very Small Embryonic-Like Stem Cells (VSEL stem cells) in 2006. These cells originate in the bone marrow and mobilize after bodily damage including brain damage from stroke, for example. These cells are released into the bloodstream where they presumably make their way to the damaged area. It is unclear what role they may serve in the healing process, but their potential for regeneration of brain and spinal cord tissue is currently under investigation.

Stem cells live in other parts of the adult body as well. Fat tissue contains stem cells that have been studied for their ability to turn into other cells, including cartilage tissue. There is a growing industry using fat stem cells to replace damaged joints. These fat stem cells are similar to mesenchymal stem cells in their potential and have not been demonstrated to regenerate spinal cord tissue.

The umbilical cord is another rich source of stem cells. After childbirth, many hospitals offer mothers the opportunity to bank their umbilical cord stem cells for some potential future use. One common use for these stem cells is for bone marrow transplants in siblings with leukemia; in fact, some mothers have purposefully borne another child in order to produce umbilical cord stem cells for their sick child. These stem cells serve to replace the bone marrow following harsh chemotherapy for leukemia and have not been considered for brain and spinal cord regeneration.

Patients have asked if it is possible to harvest stem cells from their own brain and transplant them into their spinal cord. As mentioned earlier, adult human brains possess stem cells. They live deep in the brain and can respond to damage in the nervous system with limited capacity. The problem is there is no reliable way of harvesting stem cells from the brain without causing significant damage. The endogenous stem cells make up only a small portion of the cells in the middle of the brain so they cannot be surgically cut out and saved in the lab. To even try could lead to significant neurologic disability and maybe death. However, Stem Cells Inc (Newark, CA) has created a line of neural stem cells from adult brains, which are purified and transplanted into the brains of children with Batten’s disease. Although not helpful in these children, they proved relatively safe and feasible. In December 2010, Stem Cells Inc received approval in Switzerland to proceed with a spinal cord injury trial, in which they would transplant their adult-derived human stem cells into spinal cords of 12 patients, 3 to 12 months after initial trauma. On September 22, 2011, Stem Cells Inc announced they successfully transplanted their first patient without any complications. Their hope is that these stem cells will adapt to their new environment and regenerate the damaged spinal cord.

Adult human stem cells are considered limited in their ability to adapt to the environment and develop into all of the cells necessary for regeneration. In order to make stem cells that have a broader capacity to regenerate spinal cord tissue, scientists turned to two other cell types: fetal stem cells and embryonic stem cells. Embryonic stem cells come from the early embryo, several days after fertilization of the egg. When the embryo initially grows, it divides from one egg to two cells, then to four and then eight. At this point, each of the eight cells has the capacity to become an individual. In theory, if you separated those eight cells and grew them up, they could form eight complete identical human beings. They have the capacity to become any cell type and are therefore called totipotent. After a few more days of cell division, a special group of cells, that will form the fetus, collect as the inner cell mass. These are the cells that are harvested as embryonic stem cells (Figure 1).  Typically, embryonic stem cells for research are acquired from in vitro fertilization (IVF) labs. These labs help infertile couples to have babies by fertilizing eggs in the lab and placing them into the mother’s uterus. They usually make 15-20 embryos and freeze those that are not used, usually at the 8-cell stage. When the mother decides she does not want anymore children, the lab offers the mother the choice to either destroy the remaining embryos, or send them to research labs. In research labs, the embryonic stem cells are grown under special conditions to divide into more embryonic stem cells. Under other conditions, these embryonic stem cells can be developed into different tissue types. For example, using a proprietary 42-day protocol, Geron Inc. (Menlo Park, CA) developed a method to develop transplantable neural cells that resemble oligodendroglia, cells that make myelin, from embryonic stem cells. Geron was the first company in the world to launch a clinical trial with human embryonic stem cells. After safely transplanting 4 patients with spinal cord trauma, Geron unfortunately discontinued their stem cell operations on November 14, 2011, due to financial decisions. The only other US company to develop a clinically useful cell line from human embryonic stem cells is Advanced Cell Technology (ACT, Santa Monica, CA). ACT’s protocol pushes embryonic stem cells toward becoming specialized cells in the eye for patients with macular degeneration. ACT is unique among stem cell companies because they harvest their embryonic stem cells by gently removing a single cell from an 8-cell embryo without harming the other 7 cells. This process allows the 7-cell embryo to potentially continue its development into a full human being and thus avoids the politically contentious issue of embryo destruction.

Another approach that attempts to avoid the politically contentious issue of embryo destruction was demonstrated by International Stem Cell Corp (ISSC, Carlsbad, CA) using a process called parthenogenesis. Parthenogenesis is a method of reproduction found in nature that involves the creation of an embryo from an egg without the need for fertilization, thus creating a species of female-only animals. In 2006, ISSC created a stem cell line from a human egg by chemically inducing development without fertilization. ISCC created a line of parthenogenetic stem cell lines derived from racially and ethnically diverse eggs; creating a “stem cell bank” that can be matched to recipients, which would reduce the chance of immune rejection of the transplant.  However, parthenogenesis experimentally tested in mammals tends to create non-viable organisms and the utility of these stem cells has been questioned.

Directing development of human embryonic stem cells into tissues of interest is difficult. While some companies have managed to create a few lines of specialty cells (Geron and Advanced Cell Technology, see above), the vast majority of cells in the human body cannot currently be produced in a dish from embryonic stem cells, especially for clinical use. The biology of development from an 8-cell embryo into a full human being is incredibly complex and scientists have only begun to learn how to manipulate embryonic stem cells for clinical use. In order to get a “head start” on the process, some groups have studied the potential for clinically developing stem cells from a later stage fetus. A later stage fetus possesses stem cells called fetal stem cells, which are distinct from embryonic stem cells. Fetal stem cells cannot become any tissue in the body. After the 8-cell stage, cells in the fetus are starting to become committed to a certain tissue. At each later stage, the cells in the fetus continue to develop toward that tissue and lose their embryonic cell characteristics. The timing of the harvest of fetal stem cells is critical because if they have not developed enough, the cells will not necessarily perform the task required without further culturing in the lab. If the fetal stem cells are harvested too late, they may be too committed to adapt to a new environment. Companies, such as NeuralStem (Rockville, MD), developed a line of neural stem cells from a 7-week aborted fetus and have obtained FDA approval to transplant these cells into spinal cords of patients with Lou Gehrig’s disease, in order to try to regenerate their lost motor neurons and restore neurologic function.

All of the stem cell therapy approaches mentioned above will require medications to avoid immune rejection after transplantation. Just as with solid organs, such as transplantation of kidneys or livers, the recipient’s immune system will attempt to remove the foreign transplant unless the immune system is suppressed with transplant-rejection drugs. But a new idea may potentially avoid the need for such drugs. The idea is to personalize the stem cell for each individual and create an embryonic-like cell line from the patient’s own DNA. One such approach, called cloning, is banned in the United States. Cloning involves removing the DNA from a patient’s skin cells and implanting it into an enucleated egg. The egg would contain all of the DNA necessary for life and would be an identical genetic match to the DNA donor. In theory, if this egg developed into a full human being, it would be a clone of the DNA donor. Cloning has been successfully performed in animals, including the famous Dolly the Sheep, and many cloned animals live normal, healthy lives. But in humans, cloning is fraught with ethical issues.  Americans prefer to avoid these issues and have elected to ban the process altogether.

In 2006, a Japanese scientist found another way to create a personalized stem cell line by taking skin cells from a donor and exposing the cells to four viruses containing particular genes involved in early cell development. The skin cells remarkably morphed back in time to become embryonic like again. These cells are called induced pluripotent stem cells (iPS cells) and they can be created from almost any cell, not just skin. Left in a dish, iPS cells then tended to develop back into an/the original cell type but they could be forced into another cell lineage using the right combination of growth factors and hormones. In theory, these iPS cells transplanted back into the donor would not be rejected because they are recognized as self. The problem of using viruses to create iPS cells was solved when another group showed that protein products could be used instead. iPS cells still face a significant hurdle for clinical use because by messing around with developmental genes, there is a risk that these cells will lose their sense of maturity and develop into a cancer-like cell. Extensive safety studies will need to be done with iPS cells before there is any chance they can be used in clinical trials.

In summary, interest in using stem cells to regenerate the brain and spinal cord has exploded over the past 15 years. Several clinical trials are already ongoing in the United States and Europe evaluating the safety and preliminary efficacy of different kinds of stem cells in the treatment of spinal cord trauma. None of these trials, or any other human trial of stem cells published to date, have demonstrated conclusive evidence of spinal cord or brain regeneration, although that is the goal. Many foreign companies have websites offering “stem cell trials” for treatment of MS and other neurologic disorders, but there is little or no science to back up their claims. At the Panama Stem Cell Institute, for example, the doctors will harvest mesenchymal stem cells from fat tissue and inject them back into the patient intravenously three times over the course of a week for the price of about $5000. Assuming their facilities are clean and sterile, this procedure is likely to be safe and the mesenchymal cells may positively impact the immune system to calm it down as described above. But mesenchymal stem cells from fat tissue will not lead to spinal cord or brain regeneration. Before deciding on making such a trip, consider that any previous stem cell therapy will likely disqualify a patient from participating in a US-based stem cell trial. This is because the researchers need to know the potential impact was from their stem cells and not from a previous stem cell transplant. For now, that money is better spent taking a relaxing vacation to the Panama beach instead.

There are currently no trials of stem cells to treat inflammatory or demyelinating diseases of the brain and spinal cord, but several groups, including industry and academia are working together on animal models that can be quickly translated to human trials in the near future. At Johns Hopkins, researchers at the Transverse Myelitis Center are working with NeuralStem to test the potential of neural stem cells to regenerate the spinal cord after inflammation and improve neurologic recovery in rodent models of transverse myelitis and multiple sclerosis. Similarly, they are transplanting the neural stem cells in the optic nerves to test their potential to recover vision after optic neuritis.  Because NeuralStem’s neural stem cells are already approved for safety by the FDA, the translation of these animal studies to clinical trials in humans will be much faster. The timeline of the TM group at Johns Hopkins, assuming they find success in their animal models, is to move to a human trial in transverse myelitis and optic neuritis by 2014.