A relapse-remitting multiple sclerosis patient describing his experience with adult stem cell therapy. The scientific basis for the use of fat stem cells is described here. Additionally, here is a link for a newspaper article describing stem cell therapy for multiple sclerosis.
The question of adult stem cells differentiating into needed tissue is not based on opinion but on over 2 decades of solid peer reviewed research at international academic institutions. To state there is controversy regarding the ability of adult stem cells to therapeutically augment natural healing processes, is like saying there is controversy whether red blood cells transport oxygen.
There is no question as to the scientific rationale of therapeutic benefits. The only question is the extent of the benefits and the selection of patients for undergoing stem cell therapy.
In order to understand these issues, we must first begin by understand a little bit about stem cells. We will begin with the bone marrow stem cell.
1. What is the bone marrow stem cell?
Traditionally, the bone marrow was viewed as the source of all blood cells, being responsible for production of trillions of cells per hour. Essentially one type of cell in the bone marrow, called the hematopoietic (“hematopoietic” means “blood making”) stem cells, possesses the unique ability to make copies of itself, but also, depending on the needs of the body, to make other blood cell types as well. At a molecular level we know that the human bone marrow hematopoietic stem cells expresses the markers CD34 and does not express markers of lineage commitment such as HLA-DR, CD38, CD11, CD31, etc [1]. This essentially means that bone marrow hematopoietic stem cells can be isolated and studied as a discrete entity.
The bone marrow hematopoietic stem cell adapts to the needs of the body and accordingly produces specific cell types when the body needs them. For example, when a person goes up to live on the mountains, the person’s body needs more red blood cells than usual since there is less oxygen at high altitudes. In order to compensate for this, the kidney starts to produce more erythropoietin (a hormone that travels throughout the body), which instructs the hematopoietic stem cell to produce more blood cells [2]. The same occurs in situations of infections in which the body needs more white blood cells (such as neutrophils) to protect itself against the external pathogens. In response to various molecular signals (G-CSF, GM-CSF) generated by the immune system of the person, the bone marrow hematopoietic stem cell starts to generate more white blood cells [3].
In addition to containing the cells that make blood, the bone marrow contains cells called “stromal cells” that support the hematopoietic stem cells. Essentially, stromal cells are comprised of various actual cell populations The stroma includes adipocytes, osteoblasts, and mesenchymal stem cells [4]. The primary function of mesenchymal stem cells in the bone marrow is to control proliferation of the hematopoietic stem cell, through provided growth factor support. This is why certain scientists are using mesenchymal stem cells to accelerate blood formation after administration of hematopoietic stem cells in patients [5].
Bottom line: There are two main types of stem cells found in the bone marrow: 1) hematopoietic stem cells that make blood and 2) mesenchymal stem cells that provide support for the hematopoietic stem cell.
2. Bone Marrow Transplantation: The first application of stem cell therapy.
Stem cell therapy is not new. Ever since the discovery of the hematopoietic stem cell by Drs Till and McCulloch in the 1960s, the use of these cells for transplantation into patients with defective bone marrow was envisioned. The first hematopoietic stem cell transplant, or bone marrow transplant, was performed in 1956 by Dr. E. Donnall Thomas using bone marrow cells isolated from an identical twin donor for a recipient who had leukemia. The idea was that if the patient was irradiated with high doses, then the radiation would kill all of the leukemia cells. Unfortunately, the radiation would also destroy the healthy bone marrow stem cells. So the idea was to utilize donor bone marrow to replenish the recipient with healthy hematopoietic stem cells. Dr. Thomas, along with Joseph E. Murray, won the Nobel Prize in 1990 for this discovery. The usefulness of transplanting the hematopoietic system was not limited to leukemias, in 1968, bone marrow transplantation was performed successfully on a patient with a genetic mutation called severe combined immunodeficiency. In this disease the bone marrow stem cells are deficient in ability to generate T and B cells, as a result the patient is immune compromised and is forced to live in a sterile environment. The administration of healthy bone marrow cells resulted in the child being able to function normally as a result of a non-mutated hematopoietic stem cell that is capable of making T and B cells.
Since the initial bone marrow transplant procedure was developed, several hundred thousands procedures have been performed, literally giving a new lease on life to many patients whose diseases were previously considered lethal. Variations on the theme of bone marrow transplantation have also been performed in order to increase efficacy. For example, patients with some leukemias are known to have a higher probability of relapse (leukemia coming back) after the transplant. In order to fight off the relapse, clinicians have started infusing lymphocytes from the donor as a type of cellular therapy. These Donor Lymphocyte Infusions are currently part of the accepted medical practice for treatment of post-transplant relapsed CML[6]. Additional modifications to the transplant procedure have included the use of G-CSF mobilized donor stem cells. Instead of performing puncture of the iliac crest for bone marrow aspiration, a gentler procedure that was developed involved “telling the bone marrow stem cells” to leave the bone marrow and enter systemic circulation, by the administration of the drug G-CSF. The stem cells are collected from the blood using a procedure called leukopheresis [7]. Another advancement in the area of hematopoietic stem cell transplantation has been the use of cord blood as a source of blood-forming stem cells. Cord blood stem cells express higher regenerative potential on a per-cell basis compared to bone marrow stem cells. Although cord blood stem cells are generally safer in the sense that they do not evoke graft versus host (a side effect of transplantation) with the same severity as bone marrow stem cells, cord blood stem cells are available in small numbers and therefore their use in adults is still limited to certain patient subgroups [8].
Conclusion: Stem cell therapy in the sense of hematopoietic stem cell transplantation, has been occurring since 1956 for treatment of disturbances of the blood making components of patients. These disturbances can be caused by genetic abnormalities (ie severe combined immunodeficiency, sickle cell anemia, etc) or induced as a side effect of treatment (ie dose radiation for clearing leukemia). The hematopoietic-reconstituting stem cell therapy should not be confused with stem cell therapy for regenerative medicine. In regenerative medicine the stem cells are administered in absence of the destruction of the recipient’s bone marrow hematopoietic compartment.
3. Bone Marrow and Regeneration: The Bone Marrow Cells Can Become Different Cells besides Just Blood Cells
As we described above, transfer of bone marrow stem cells has been performed for decades. Scientists have wondered, if the bone marrow stem cell possesses the potential to differentiate into all the different types of blood cells, maybe it can also differentiate into other cells as well. This process was originally termed “transdifferentiation”. The first report of transdifferentiation to appear in the major medical literature was a paper by Orlic et al. [9], in which mouse bone marrow derived stem cells were injected into mice that were given an experimental heart attack. The interesting thing about this experiment was that the bone marrow stem cells used were labeled to glow green. The donor animals were genetically engineered to express the green fluorescent protein (GFP) gene throughout their bodies. This essentially means that all cells derived from the GFP donor mice were green. Additionally, the experimenters purified the mouse equivalent of the human CD34 bone marrow hematopoietic stem cell. The molecular markers used where positivity for stem cell antigen (SCA-1) and negativity for the lineage markers (lin negative). Following induction of a heart attack by ligation of one of the coronary arteries, the researchers implanted the cells in the area of infarct. The mice which received implanted hematopoietic stem cells, but not control cells, had increased pumping ability of the heart and decreased levels of heart damage. Most interestingly, when mice where sacrificed, green cells were observed throughout the area of damage.
This paper served as a strong indication in animals that bone marrow derived cells are capable of differentiating into heart tissue and helping to repair injury. Eventually scientists started finding that bone marrow stem cells can differentiate into other tissues. For example, human bone marrow derived CD34 cells have been demonstrated to differentiate into cells expressing liver markers, and can actually generate human liver proteins when injected into animals [10].
The concept of bone marrow cells differentiating into cells other than hematopoietic cells has subsequently been demonstrated in numerous laboratories for many types of tissues. The table below summarizes some of the tissues. We will include both hematopoietic and mesenchymal stem cells in the analysis since both are found in the bone marrow. It is important to make a note that some researchers believe embryonic stem cells are the only cell types capable of differentiation into different tissues. While it is true that embryonic stem cells indeed are “totipotent”, these cells are very far from clinical use. Injection of embryonic stem cells into animals causes a type of aggressive tumor called “teratomas” [11], and furthermore, the differentiation of these cells is difficult to control. In other words if you want to generate livers cells from embryonic stem cells, and you add liver-induction factors, such as hepatocyte growth factor, some cells become liver, but other cells still become neurons, kidney cells, and skin cells, thus until science advances, adult stem cells still seem to be superior for clinical applications.
4. Importance of Bone Marrow Resident Stem Cells for Natural Repair of Tissue Injury
The examples above, as well as the published literature, demonstrate in an unequivocal manner that bone marrow derived cells have a certain amount of plasticity, or ability or ability to differentiate into non-hematopoietic tissues.
The main idea being that bone marrow can differentiate into a variety of tissues. Now why would the bone marrow have this ability? One theory is that the bone marrow acts as a reserve of “regenerative cells” that are important in healing the body as the body ages. The ability to regenerate is most potently seen in the salamander, which can regenerate whole limbs, based on potent stem cell activity. Although humans do not have regenerative activity that potent, there are still evidences that bone marrow stem cells do in fact contribute to regeneration. First we will provide an in vivo example of bone marrow “transdifferentiating” into other tissues in the human, and then we will provide examples of bone marrow helping in healing processes.
As we discussed above, bone marrow transplantation is performed for hematological disorders, one of which is leukemia. Now if a female receives a male bone marrow transplant, one would imagine that the circulating blood cells of the female have the Y chromosome, which is correct. What is more interesting is whether tissues in the female’s body actually start to express the Y chromosome. In a very interesting study [12], researchers performed autopsy on female patients who had received male bone marrow transplants. When they examined the heart tissue, the female heart tissue contained cardiac muscles that had the Y-chromosome !! This conclusively demonstrates that in normal situations bone marrow derived cells differentiate to become different parts of the body. Similar findings were also reported in liver, pancreas, and kidney.
Now what about in situations of heart attacks? One would imagine that during a heart attack, bone marrow derived stem cells would migrate into the heart. If this is indeed the case, then taking blood samples of patients after heart attacks should demonstrate increases in stem cells. Indeed numerous studies have shown this to be the case. Below is an example from one study [13].
A similar argument can be made in stroke. Interestingly, in stroke, there has been reported an association between higher degree of mobilization and improved recovery as assessed by the NIHSS score [14].
From the examples presented above, as well as numerous other publications, endogenous bone marrow stem cells have been demonstrated to play a regenerative role in humans. The next question is whether the administration of bone marrow stem cell therapy can actually induce a clinical effect?
5. Clinical Examples of Bone Marrow Stem Cell Therapy for Regeneration
Bone marrow stem cell therapy for regenerative (non-hematopoietic) purposes originally started with Japanese research when bone marrow cells were injected into the heart muscle of patients undergoing bypass surgery. The idea was that the injected bone marrow cells will stimulate production of new blood vessels and thereby increase oxygenation to the heart [15]. The procedure, although highly invasive, was associated with no treatment related adverse effects and 3 out of the 5 patients had increased blood vessel production as assessed radiologically, as well as improved cardiac function. This first demonstration in 2001, was repeated by numerous investigators. In 2003, the study was repeated using CD133 purified bone marrow stem cells and published in the prestigious journal Lancet [16], reporting positive results. Subsequently numerous studies have been conducted in the area of cardiology demonstrating that administration of a patient’s own bone marrow is associated with positive outcome. For example, there are published pictures of myocardial activity before and after stem cell therapy from a clinical study [17].
Convincingly, statistically significant improvements in left ventricular ejection fraction have been observed in double blind trials. For example there is published from a 200 patient trial [18].
In addition to the heart, bone marrow stem cells have been used for numerous other indications clinically. One interesting indication is critical limb ischemia, which involves occlusion of blood flow to the lower limbs and is associated with need for amputation. Below is a representative angiogram from a patient before and after bone marrow stem cell therapy as part of a double blind trial [19]. Additionally, in the same trial, clinical endpoints such as ankle brachial index (how much blood flows to the leg), pain-free walking, and transcutanous oxygen where all increased in a statistically significant manner.
Bone marrow stem cells have also been demonstrated to be effective in regeneration of other damaged/degenerated organs. In a clinical trial with 9 patients suffering from liver failure [20], the administration of their own bone marrow cells intravenously elicited restoration in albumin production as seen in the figure below. Each line in the figure represents one patient. As well as overall decrease in clinical severity of disease (Child Pugh Score).
6. Bone Marrow Derived Mesenchymal Stem Cells
The clinical examples above were aimed at fresh, non-cultured bone marrow derived stem cells. Since it is difficult to enforce patents on medical procedures, numerous companies have developed “universal donor” off the shelf, stem cells that have been cultured in vitro and can be sold as “medicines”. Of the companies activity in this area (Neuronyx, www.neuronyx.com in Phase I clinical trials, Pluristem, www.pluristem.com in late preclinical, and Osiris Therapeutics, www.osiris.com, 2 phase IIIs, several phase II trials), Osiris therapeutics has been the clear-cut leader, anticipated to have a product on the US market in the near future. Below is a summary data of Osiris’s bone marrow mesenchymal stem cells used to treat Crohn’s Disease. Survival figures in patients treated with mesenchymal stem cells for a lethal inflammatory disease called are well published in the case of GVHD [21].
7. Conclusion: Bone Marrow Stem Cell Therapy…Enhancing the Body’s Regenerative Potential
Dr. Thomas would be proud. From the initial bone marrow “cell therapy” transplant in 1956, the use of bone marrow stem cells has expanded to cover almost any indication one could imagine. One only has to look at the www.clinicaltrials.gov database to see that clinical applications of bone marrow cells are being tested in conditions ranging from heart disease, to autoimmunity, to neurological conditions.
The wide applicability of bone marrow stem cells to so many diseases comes from the fact that stem cell therapy is only an augmentation of the natural regenerative processes. It is established that injured or damaged tissue releases distinct factors that “call in” bone marrow stem cells. By administering the cells in high concentrations intravenously, or locally, the bone marrow stem cell therapist is only helping the body to do what it is trying to do…to heal itself.
References
1. Srour, E.F., et al., Human CD34+ HLA-DR- bone marrow cells contain progenitor cells capable of self-renewal, multilineage differentiation, and long-term in vitro hematopoiesis. Blood Cells, 1991. 17(2): p. 287-95.
2. Berglund, B., High-altitude training. Aspects of haematological adaptation. Sports Med, 1992. 14(5): p. 289-303.
3. Lee, K.Y., et al., Varying expression levels of colony stimulating factor receptors in disease states and different leukocytes. Exp Mol Med, 2000. 32(4): p. 210-5.
4. Krebsbach, P.H., et al., Bone marrow stromal cells: characterization and clinical application. Crit Rev Oral Biol Med, 1999. 10(2): p. 165-81.
5. Koc, O.N., et al., Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol, 2000. 18(2): p. 307-16.
6. Dazzi, F. and C. Fozza, Disease relapse after haematopoietic stem cell transplantation: risk factors and treatment. Best Pract Res Clin Haematol, 2007. 20(2): p. 311-27.
7. Levesque, J.P., et al., Mobilization of bone marrow-derived progenitors. Handb Exp Pharmacol, 2007(180): p. 3-36.
8. Riordan, N.H., et al., Cord blood in regenerative medicine: do we need immune suppression? J Transl Med, 2007. 5: p. 8.
9. Orlic, D., et al., Bone marrow cells regenerate infarcted myocardium. Nature, 2001. 410(6829): p. 701-5.
10. Wang, X., et al., Albumin-expressing hepatocyte-like cells develop in the livers of immune-deficient mice that received transplants of highly purified human hematopoietic stem cells. Blood, 2003. 101(10): p. 4201-8.
11. Nussbaum, J., et al., Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J, 2007. 21(7): p. 1345-57.
12. Deb, A., et al., Bone marrow-derived cardiomyocytes are present in adult human heart: A study of gender-mismatched bone marrow transplantation patients. Circulation, 2003. 107(9): p. 1247-9.
13. Muller-Ehmsen, J., et al., The mobilization of CD34 positive mononuclear cells after myocardial infarction is abolished by revascularization of the culprit vessel. Int J Cardiol, 2005. 103(1): p. 7-11.
14. Dunac, A., et al., Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization. J Neurol, 2007. 254(3): p. 327-32.
15. Hamano, K., et al., Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: clinical trial and preliminary results. Jpn Circ J, 2001. 65(9): p. 845-7.
16. Stamm, C., et al., Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet, 2003. 361(9351): p. 45-6.
17. Stamm, C., et al., Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: safety and efficacy studies. J Thorac Cardiovasc Surg, 2007. 133(3): p. 717-25.
18. Schachinger, V., et al., Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med, 2006. 355(12): p. 1210-21.
19. Tateishi-Yuyama, E., et al., Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet, 2002. 360(9331): p. 427-35.
20. Terai, S., et al., Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells, 2006. 24(10): p. 2292-8.
21. Ringden, O., et al., Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation, 2006. 81(10): p. 1390-7.
A point of confusion regarding “stem cell therapy” for multiple sclerosis comes from two very different types of approaches that both use stem cells. The first approach is the use of stem cells WITHOUT depleting the recipient immune system, the second approach involves administration of stem cells AFTER depleting of the immune system.
The first approach usually involves mesenchymal stem cells, such as found in the patient’s own fat, but has also been performed with cord blood. The rationale for using stem cells in the absence of immune suppression is that the stem cells may help to regenerate the injured tissue, and also that they may suppress the autoreactive immune response. Another interesting feature of mesenchymal stem cells is that they specifically “react” to their environment. In other words, mesenchymal stem cells produce a certain level of antiinflammatory compounds when they are grown in tissue culture by themselves, however, when they are treated with compounds that cause inflammation, such as TNF-alpha, then they markedly upregulate their production of antiinflammatory agents such as IL-10, and also start producing more growth factors such as IGF-1. This is believed to be because the mesenchymal stem cell normally acts as a “repair cell”. That is, when there is tissue injury in the body, the mesenchymal stem cells naturally migrate to the injury (by virtue of proteins called chemokines) and then play a fundamental role in the healing process.
The second approach to treatment of multiple sclerosis by stem cells focuses on “reprogramming” the immune system. Stem cells used for this are the stem cells that make blood, called “hematopoietic” stem cells. In other words, we know that in multiple sclerosis there are numerous T cells that are attacking the body, and specifically the myelin sheath of the central nervous system. These “bad” T cells have not only been identified but vaccines have been made with them. Well instead of selectively killing some specific T cells, or only killing the activated T cells (like daclizumab does), the process of using stem cells with immune depletion involves first killing ALL immune cells, and secondly restoration of the immune cells by administering the patient’s own purified hematopoietic (blood making) stem cells. By readministering the patient’s own stem cells in absence of T cells, the body is left to make its own T cells again from scratch. Theoretically this is very appealing. Practically there are a couple of problems. First of all, the period of time from when the patient’s immune system is destroyed artificially (usually by chemotherapy and/or irradiation), to when the administered stem cells make new immune cells, leaves the patient exposed to many bacteria and viruses. Secondly, there is a phenomena called “homeostatic expansion” in immunology. This is explained in this video. Essentially, when a small number of immune cells are placed in a host that lacks immune cells, the few immune cells start to multiple aggressively and lose ability to be regulated by normal mechanisms that stop the body from attacking itself. In autologous transplantation with immune depletion, purified stem cells are reintroduced to the patient, so this should not be a problem, however, even a small amount of T cell contamination could potentially cause exacerbated disease. The third danger with this approach is that when the stem cells are given to the patient that is lacking an immune system, the new T cells need to be made in the same way that the T cells were made from stem cells when the patient was young. See, T cells only get made before you are born, primarily because of bone marrow hematopoietic stem cells migrating to the thymus and making new T cells in the thymus. After puberty the thymus becomes much smaller and loses a lot of its functional ability. This is because almost no new T cells are made after puberty. So when you destroy the immune system and “ask” the hematopoietic stem cell to regenerate a brand new population of T cells, these T cells are made in a thymus that is severely atrophied. Therefore the new T cells may have many potential abnormalities.
The two stem cell approaches (without destruction of the recipient immune response and with it) are discussed in a recent publication (Muraro et al. Immuno-Therapeutic Potential of Haematopoietic and Mesenchymal Stem Cell Transplantation in MS. Results Prob Cell Differ 2009 Jan 23).
The authors review how hematopoietic stem cell transplantation (involving immune destruction) has been used for more than 40 years for treatments of leukemias, and is now expanding into the area of autoimmune diseases, not only multiple sclerosis, but also rheumatoid arthritis and type 1 diabetes. According to the paper, the highest number of hematopoietic stem cell transplants for autoimmunity has actually been performed in multiple sclerosis.
In multiple sclerosis, hematopoietic stem cell transplants appear to stop acute inflammation in the central nervous system and prevent relapses. Unfortunately, limited to no effect is seen in patients with secondary progressive multiple sclerosis.
The article then goes on to talk about non-immune depleting transplants, specifically focusing on mesenchymal stem cells. It states that the original idea with using mesenchymal stem cells was that they can differentiate into myelin producing oligodendrocytes and neurons, but now most people believe that the mechanism of action of these cells is primarily mediated by modulation of the immune system.
Currently clinical trials are being conducted using mesenchymal stem cells that have been culture-expanded and hematopoietic stem cells with destruction of the immune system before placement. It will be interesting to see which ones have better effects. Of course the period of immune destruction before administration of the hematopoietic stem cells has the potential to cause numerous adverse effects. Therefore, places like StemNow.com exclusively offer therapies that do not involve destruction of the immune system before stem cell administration.
Multiple sclerosis is an autoimmune disease in which the patient’s immune system begins attacking the lining of the nerves called the myelin sheath.
There are two main problems that need to be addressed in MS: a) how to stop the misdirected immune attack and b) how to repair the damage that has already been caused.
Currently available therapies are directed towards non-specifically suppressing the immune system so that ongoing nervous system destruction is prevented. The drawback being that immune suppression exposes the patient to various other pathogens.
Mesenchymal stem cells (MSC) have been demonstrated in numerous animal models and clinical trials to inhibit pathological immune responses while stimulating regeneration of damaged nerve tissue. In clinical trials, bone marrow derived MSC have passed Phase I safety studies and are currently in a number of Phase II and III efficacy studies.
Stemnow.com offers the therapy using the patient’s own fat derived cells which contain not only MSC but also several therapeutic cell populations.
Background: In healthy people, the immune response is fine-tuned so as to specifically be able to destroy foreign pathogens, while at the same time have the ability to know that it should not turn against the body. For reasons that are not completely understood, some patients developed “autoimmune” diseases in which the immune system starts attacking tissues of the body. In multiple sclerosis this is manifested through destruction of the myelin sheath that insulates nerves in the white matter of the brain. This destruction is observed by MRI in the form of plaques, and functionally is manifested by the patient experiencing the various characteristics of MS ranging from visual (e.g. optic neuritis, nystagmus, etc), motor (e.g. paresis, spasticity, etc), sensory (e.g. paraesthesia), balance (e.g. ataxia, vertigo) and cognitive (depression, cognitive dysfunction) alterations.
There are 4 main types of MS: 1) Relapse-remitting MS is the condition which the majority (about 85-90%) of MS patients are initially diagnosed with. As the name indicates, this type is characterized by relapses followed by periods of remission in which disease activity subsides. It is believed that during remission the oligodendrocytes “fix” the neurons by producing new myelin; 2) Secondary progressive MS usually occurs as a progression of the relapse remitting type at the point where remissions decrease in frequency and eventually the debilitating characteristics continually progress. On average it takes about 19 years for MS to convert from relapse-remitting to secondary progressive; 3) Primary progressive is characterized by patients presenting with MS in which no remissions are seen; and 4) In the progressive relapsing form, a continuous increase in symptoms is seen, however spikes of accelerated disease activity are interspersed in the progression of the condition.
Depending on the type of MS, various treatments are routinely used. These include steroids, immune suppressants (cyclosporine, azathioprine, methotrexate), immune modulators (interferons, glatiramer acetate), and immune modulating antibodies (natalizumab). The general treatment concept is to rapidly treat relapses so as to minimize permanent damage, as well as to prevent onset of relapse or progression to more advanced forms of MS. Unfortunately long term efficacy data is not available for many of the current approaches used clinically. At present none of the MS treatment available on the market selectively inhibit the immune attack against the nervous system, nor do they stimulate regeneration of previously damaged tissue. Experimental approaches in clinical trials are trying to use a peptide vaccine to specifically inhibit anti-myelin immune responses by the company BioMS, however even if successful this approach will not induce regeneration. Other experimental approaches include the use of bone marrow stem cells in combination with chemotherapy to destroy the original immune system of the patient and subsequently attempt to restart it. Needless to say this procedure has the possibility of adverse effects. We use another type of stem cell therapy that does not involve chemotherapy or destruction of the immune system, instead it involves a “re-education” through administration of mesenchymal stem cells that concurrently inhibit pathological immunity while stimulating regeneration of damaged neural tissue.
Rationale: Mesenchymal stem cells are a type of cell that possesses potent immune regulatory activity. It has been demonstrated in clinical trials that patients suffering from deregulated immune responses, such as in Crohn’s Disease or Graft Versus Host Disease go into remission after administration of mesenchymal stem cells (www.osiris.com).
Unlike conventional immune suppressive drugs that act everywhere in the body, mesenchymal stem cells possess the ability to “home” to areas of inflammation and specifically shut off immune responses that are harming the body. Various molecules secreted by injured tissues such as FGF-2 are known to chemoattract mesenchymal stem cells. Additionally, during pathological immune responses, such as in multiple sclerosis, the molecule interferon gamma is produced. Mesenchymal stem cells “sense” interferon gamma production and become more immune suppressive in response to it (Ryan et al. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol. 2007 May 22).
One way that mesenchymal stem cells locally shut down pathological immune responses is through blocking T cell proliferation. This occurs through a variety of mechanisms, one being activation of the immune suppressive enzyme indolamine 2,3 deoxygenase (Meisel et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004 Jun 15;103(12):4619-21).
Additionally, mesenchymal stem cells are known to induce generation of an immune suppressive population of T cells called T regulatory cells (Maccario et al. haematologica 2005; 90(4). These cells are known to protect the body against autoimmunity and act in a specific manner to inhibit pathological but not healthy immune responses. Specific inhibition of pathological immunity in mouse models of multiple sclerosis has also been reported by mesenchymal stem cells (Zappia et al. Blood, 1 September 2005, Vol. 106, No. 5, pp. 1755-1761).
In addition to blocking such autoreactivity, mesenchymal stem cells have been demonstrated to:
a) Accelerate remyelination (Keilhoff et al. Transdifferentiated mesenchymal stem cells as alternative therapy in supporting nerve regeneration and myelination. Cell Mol Neurobiol. 2006 Oct-Nov;26(7-8):1235-52);
b) Prevent neuronal apoptosis (Caplan et al. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006 Aug 1;98(5):1076-84);
c) Directly differentiate into neurons (Muñoz-Elías et al. Marrow stromal cells, mitosis, and neuronal differentiation: stem cell and precursor functions. Stem Cells. 2003;21(4):437-48)
d) Induce endogenous neural stem cells activation to regenerate new neurons (Caplan et al. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006 Aug 1;98(5):1076-84).
Since mesenchymal stem cells promote nervous system repair through several synergistic mechanisms, these cells possess a much higher probability of success as opposed to other gene or cytokine therapies in which only one reparative mechanism is being activated. In fact, these cells are known to produce a wide number of trophic growth factors themselves which assist in neural regeneration.
Clinical Implementation: The dual role of mesenchymal stem cells for blocking pathological immunity while inducing regeneration of neural tissue that has already been damaged has already been described (Uccelli et al. Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection. Expert Opin Biol Ther. 2006 Jan;6(1):17-22). Animal studies and case reports are supportive of this approach. In fact, a clinical trial is currently ongoing at the University of Cambridge utilizing mesenchymal stem cells for multiple sclerosis. We have treated numerous patients with mesenchymal stem cells with no evidence of adverse events or immune reactions. Some of the patient experiences in our hands can be seen in our recent publication.
Cleveland, Ohio -
The possibility of stem cells treating multiple sclerosis is very enticing.
This comes from two angles. The first is that various type of stem cells either directly can heal injured nervous system tissue or produce various growth factors that allow the injured tissue to heal itself. For example, it has been published that mesenchymal stem cells can differentiate into oligodendrocytes, which make myelin. It has also been reported that stem cells produce growth factors such as IGF-1, which when administered into injured central nervous system tissue cause its repair. The second reason why stem cell therapy for multiple sclerosis is appealing is that various types of stem cells, such as mesenchymal stem cells, are known to have immune modulating properties. In other words, since multiple sclerosis is mediated by an abnormal T cell response, there is a possibility that therapy using cells such as mesenchymal stem cells may actually not only heal the damage that has occurred, but also address the root cause of the damage.
There was a recent paper (Bai et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis) which used human bone marrow mesenchymal stem cells to treat mice which were induced to have a disease that is similar to multiple sclerosis.
The scientists used two types of mouse multiple sclerosis. The first is a progressive type, in which the MOG peptide was used to ”immunize” B6 mice, and the second is a relapse-remitting type in which another myelin component called PLP was used to “immunize” SJL mice. What this means is that the mice develop an immune response against components of the myelin, and subsequently exhibit a disease that resembles clinical multiple sclerosis.
Administration of human bone marrow derived mesenchymal stem cells into these mice resulted in reduction in disease progression, as well as healing at the cellular level. Increased numbers of oligodendrocytes (the cells that make myelin) were observed in the mice that recieved stem cell therapy. Interestingly, the autoimmune response seemed to be suppressed, well at least the inflammatory component of it, since reduction of interferon gamma and interleukin-17 was seen, which are both associated with poor patient prognosis, whereas elevated levels of interleukin-4, an antiinflammatory agent were seen in the treated mice.
This paper was particularly interesting since it demonstrated that human mesenchymal stem cells work in mice, not only for modulating the immune system but also for accelerating repair. Although not assessed, it is possible that the mesenchymal stem cells were also increasing levels of T regulatory cells. This is something that should be performed in future studies.