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Autism
Autism is a complex brain developmental disorder that is characterised by impaired social interactions, communication difficulties, obsessive attachment to routines and repetition, and often an extreme dislike of certain sounds, textures and tastes. Autism usually surfaces in the first three years of life and may vary in severity from mild to disabling. Depending on degree of severity, some children with autism may develop into independent adults with full time employment and self-sufficiency; however this is seldom the case (2). There is no known single cause but abnormalities in brain function are generally attributed to environmental, immunological and neurological factors.

Social costs
It is reported as one of the fastest-growing developmental disabilities in the US, with diagnoses having increased by staggering proportions in the last decade (2). An estimated 1.5 million children and adults in the U.S. currently (as at 2007) have some form of autism (2). Presenting these statistics another way; autism spectrum disorders are believed to affect approximately 1 in 166 children (1).

Children with autism suffer from two major conditions: Hypoperfusion and Immune Dysregulation

Hypoperfusion of the brain in autism

Children with autism have shown impaired blood flow (hypoperfusion) to the brain. Hypoperfusion may contribute to functional defects not only by inducing hypoxia (an oxygen deficit that prevents normal brain function) but also by allowing for abnormal metabolite or neurotransmitter accumulation. Hypothetically, if perfusion can be improved through the revitalisation of blood vessels (angiogenesis), then this should also allow for metabolite clearance and restoration of functionality.

Immune dysregulation in autism
Successful neurodevelopment is contingent upon a normal balanced immune response. Children with autism have immune systems that do not function normally; instead an autoimmune response of the nervous system appears to prevail (3). Astrocytes (supportive brain cells) that normally play a critical role in regulating perfusion [reviewed in 1] and protection against central nervous system infection, have the potential to cause damage to the host when functioning in an aberrant (i.e. auto-immune) manner. Autistic children often have continually suppressed immune systems and chronic inflammation. Immune dysregulation is very apparent in gastrointestinal health - most autistics experience symptoms ranging from diarrhea, gas, and bloating to intestinal lesions and inflammation of their gastrointestinal system (3,4).

Autism treatments
At this time there is no universally-accepted therapy or cure for autism. Current approaches are either behavioural, medical (treatment of anxiety and depression), nutritional (restriction of allergy-associated dietary components/ supplementation of minerals and vitamins/antioxidant therapy) or a combination of these. Research has increasingly focused on the connections between the immune system and the nervous system (4) yet to date no approach has been successful in correcting immune dysregulation/chronic inflammation in autism.

Rationale for using Stem Cells to treat autism
The administration of CD34+ umbilical cord cells and mesenchymal cells are proposed as novel treatments for the two pathologies associated with autism – hypoperfusion to the brain and immune dysregulation (1). Using these two kinds of stem cells together may potentially heal both the brain and the gut (3,4).

Treatment of hypoperfusion defect with umbilical cord blood CD34+ stem cells
Angiogenesis - the formation of collateral blood vessels - is believed to be fundamental in neurological recovery. A promising method of increasing angiogenesis into damaged areas is by administration of CD34+ stem cells [reviewed in 1]. Umbilical cord blood has highly active CD34+ cells that, following injection into a patient, should induce angiogenesis in areas of cerebral hypoperfusion. Consequently improved blood flow and oxygen to the brain should also improve nervous system functioning.
Safety: Allogeneic cord blood CD34+ cells are needed if this therapy is to be made available for widespread use because few, if any, patients will have access to autologous cord blood. Safety concerns regarding allogeneic CD34+ cells centre on fears of graft / host reactions. It is believed that allogeneic cord blood cells can not be used without immune suppression however Riordan et al (6) have recently published an account of the feasibility of cord blood cells administration in absence of immune suppression. Also, there are reports of stem cell treatments where no immune suppression was used in over 500 patients without a single one suffering graft vs. host disease [reviewed in 1].

Immune modulation by mesenchymal stem cells
The treatment of immune dysregulation in autism is expected to profoundly influence neurological function. The ability of mesenchymal stem cells to suppress pathological immune responses (e.g. inflammation) and to stimulate haematopoiesis (blood cell regeneration) leads to the possibility that these cells may also be useful for treatment of the defect in T cell numbers associated with autism(3).
Safety: The review by Ichim et al (1) suggests that allogeneic mesenchymal stem cells administered to suppress inflammation may be used without fear of immune-mediated rejection.

Practical clinical entry
The following passage is quoted directly from the authors’ proposal in ‘Stem Cell Therapy for Autism’(1) and outlines their suggestions for clinical trials : “We propose a Phase I/II study investigating a combination of cord blood expanded CD34+ cells together with mesenchymal stem cells for the treatment of autism and clinical manifestations of inflammatory intestinal disease. One of the authors (*Fabio Solano) has utilized both CD34+ and mesenchymal stem cells clinically for treatment of various diseases. In some case reports, the combination of CD34+ and mesenchymal stem cells was noted to induce synergistic effects in neurological diseases, although the numbers of patients are far too low to draw any conclusions. We propose to conduct this study based on the previous experiences of our group in this field, as well as numerous other groups that have generated anecdotal evidence of stem cell therapy for autism but have not published in conventional journals. We believe that through development of a potent clinical study with appropriate endpoints, much will be learned about the pathophysiology of autism regardless of trial outcome.”

Cautionary arguments
While the rationale for using stem cells to treat autism is indeed sound, many proponents of stem cell treatment for autism (6,7,8,9) are in agreement that clinical trials with sufficient patient numbers are needed to assess treatment efficacy. When patients and their families consider new treatments, the proposals need to be interpreted in a discerning manner that can be balanced with scientific evidence.

REFERENCES
1. Review: Stem Cell Therapy for Autism Thomas Ichim, Fabio Solano, Eduardo Glenn, Frank Morales, Leonard Smith, George Zabrecky, Neil H Riordan Journal of Translational Medicine June 2007, 5:30 http://www.translational-medicine.com/content/5/1/30
2. Alliance for stem cell research www.curesforcalifornia.com
3. The immune response in autism: a new frontier for autism research Paul Ashwood, Sharifia Wills, Judy vd Water Journal of Leukocyte Biology. 80:1–15; 2006
4. The Stem Cell and Autism Connection www.bodyecology.com
5. Autism www.stemcelltherapies.org
6. Cord blood in regenerative medicine: do we need immune suppression? Riordan N, Chan K, Marleau A, Ichim T. Journal of Translational Medicine. Jan 2007 5:8
7. www.autismvox.com/another-autism-treatment-stem-cell-therapy Kristina Chew, July 2007
8. www.cellmedicine.com (publication is equivalent to Review: Stem Cell Therapy for Autism Ichim et al.)
9. Osiris www.osiris.com

New advances in medical technology are increasing the options of dealing with medical conditions like cerebral palsy. One of the current thoughts concerning this rare, yet serious, medical condition is the relationship between Cerebral Palsy and Stem Cells treatment. Some medical professionals have put forward the idea that Stem Cell Treatment may be a way to prevent cerebral palsy when it is first detected. While there has been a lot of debate concerning stem cell treatments in the past and today, one must look at the possibilities of it being able to cure a multitude of different congenital conditions like cerebral palsy.

Cerebral palsy is a general umbrella term that is used to refer to a group of non-contagious diseases that are non-progressive and that create a disability in physical human development. The name of the disorder is quite descriptive. Cerebral refers to the part of the brain that is affected, which is the cerebrum. Even though the cerebrum is identified, researchers are not completely sure of the exact centre of the disorder and believe that there may be a connection to other parts of the brain, most notably the cerebellum. Palsy refers to the disability of movement and motor functions. A large percentage of cerebral palsy cases are unknown but some may occur due to damage the motor control centers of the fetus' brain during pregnancy, childbirth of after birth. In a few cases, early childhood accidents or incident such as infections, malnutrition or serious head trauma can also result in cerebral palsy. Stem Cells research has indicated that it might be able to help in cerebral palsy cases.

As of yet there is no specific cure for cerebral palsy. Stem Cells treatments, while being a possible option, are having trouble with any serious research because of public opinion towards stem cell research. Even though no 'cure' exists for cerebral palsy, advances in various therapies can allow a person suffering from cerebral palsy to go on living an almost normal life if the condition is properly managed from an early age. The most important thing is to start as early as possible with therapy so that a child can quickly learn ways to overcome his or her disabilities. There are many treatments and options available and some of them are physical therapy, occupational therapy, speech therapy, seizure control drugs, corrective surgery, communication aids and many more. Most of the treatments focus on the specific symptoms a patient exhibits and they focus on helping a person to develop what they have and how to overcome any problems.

Cerebral palsy is not a life ending problem. There is a light at the end of the tunnel and there are many peopl alive today who have overcome their disabilities and made a success of their life. A strong support from family and friends and controlled assistance for the symptoms can do wonders. Cerebral Palsy and Stem Cells research is still a debated topic. Perhaps one day, this controversial method may create a cure for this problem.

Cardiovascular disease is the leading cause of death for both men and women in the U.S. Approximately one million people die of cardiovascular disease annually despite medical intervention, with coronary artery disease claiming 50 percent of those lives.(1) Although heart disease impacts an older population whose heart muscle, arteries and pumping function have deteriorated over time, heart ailments also strike the very young. According to the National Institutes of Health, congenital heart disease is responsible for more deaths in the first year of life than any other birth defect.(2)

To date, there is no proven "off-the-shelf" therapy to repair or regenerate the heart after acute myocardial infarction (heart attack) or congestive heart failure. Because heart cells have a limited capacity to regenerate, researchers are exploring potential therapies using various stem cell sources to repair or replace damaged tissue including vascular endothelial cells, which form the inner lining of new blood vessels, and cardiomyocytes, the heart muscle cells that contract to pump blood into and out of the heart.(3)

The stem cells found in a newborn's umbilical cord blood are one type of stem cell holding great promise in cardiovascular repair. Stem cells from cord blood may have an advantage over those found in bone marrow or peripheral blood because they are immunologically "younger" and appear to be more versatile. They also demonstrate an important characteristic with embryonic stem cells: they are able to differentiate into nearly all cell types in the body. However, cord blood stem cells offer important advantages: 1)they do this in a safe and controlled manner; 2)they have been used in clinical practice to treat humans for more than 20 years; and 3)there is no controversy involved in their collection.

Researchers are noting several positive observations in pre-clinical animal studies. Thus far, in animal models, cord blood stem cells have shown the ability to selectively migrate to injured cardiac tissue, improve vascular function and blood flow at the site of injury, and improve overall heart function.(1)

Repairing Blood Vessels and Improving Ventricular Function

The heart demands a large volume of blood flow in order to bring nutrients and oxygen to the muscle tissue after it has been damaged. Research demonstrates that cord blood stem cells are capable of giving rise to vascular endothelial-like cells, which are believed to aid in the repair of heart tissue damage due to myocardial infarction. Several pre-clinical studies of induced myocardial infarction in rats have shown that cord blood stem cells have the ability to:

- Migrate and engraft to damaged heart muscle (4,5)
- Contribute to the formation and proliferation of new blood vessels (4,6)
- Improve left ventricular remodeling, structural damage and function (7)
- Decrease the size of infarction (8)

These animal studies may lay the foundation for future human clinical trials testing cord blood stem cell treatment for patients with heart damage due to myocardial infarction.

Cardiomyocytes and Cord Blood: In Vitro Studies Show Promise

Permanent loss of cardiomyocytes (heart muscle cells) and the formation of scar tissue following a heart attack result in irreversible damage to cardiac function. Human cord blood contains several different types of stem cells including hematopoietic, endothelial and mesenchymal stem cells. Although still in early stages, four in vitro studies have shown that under certain treatment conditions, cord blood mesenchymal stem cells differentiate into cardiomyocyte-like cells (9,10,11,12) and were able to induce regeneration of healthy cells from damaged cardiomyocytes (12). This suggests that cord blood stem cells have a high potential to differentiate into cardiomyocytes and aid the regeneration of cardiomyocytes lost due to heart damage.

Cord Blood and Congenital Heart Defects

Although more research needs to be done, scientists believe cord blood stem cells may have the most immediate benefit for children born with congenital heart defects - or problems with the heart's structure that are present at birth.

According to one in vitro study, cord blood endothelial stem cells demonstrated excellent growth potential for tissue-engineered vascular grafts that could replace human heart defects. These findings offer a compelling reason why parents with a child diagnosed intrauterinely with congenital defects should consider preserving their child's cord blood, since it may offer a treatment option in the future.(13)

Advances in Peripheral Vascular Disease

The ability of cord blood stem cells to become vascular endothelial-like cells and thus, blood vessels, indicates they will likely have potential applications beyond the heart.

Peripheral vascular disease (PVD) is a restriction of blood flow outside of the heart usually occurring in the legs and arms. Restricted blood flow is caused by blood vessel narrowing from fatty plaque formation on vessel walls (atherosclerosis) or blockage due to blood clots. If the blockage is severe enough, tissue death can occur. If left untreated, the limb may need to be amputated.(14)

In animal models, cord blood stem cells have been able to significantly reverse the effects of ischemia, or loss of blood flow in the blood vessels. In models of hind limb ischemia, transplantation of cord blood stem cells appeared to reverse surgery-induced ischemia resulting in limb salvage.(15-16) These observations may lead to future human clinical trials using cord blood stem cells to treat patients with peripheral vascular disease.

The Future of Cord Blood Stem Cell Therapy

As science advances, so do the number of preserved cord blood units being used in regenerative medicine applications. If expectant parents store their baby's cord blood in a family bank, the stem cells are immediately available for use in medical treatments, including future therapies to repair or replace damaged heart tissues. As a result, an infant's cord blood could prove to be a life-saving treatment option if that child is born with a congenital heart defect, or later in life following a sudden and serious heart attack. In regenerative medicine, the latest scientific evidence suggests that using one's own stem cells likely delivers more favorable outcomes.

References

1. Harris DT, Badowski M, Ahmad N, Gaballa MA. The potential of cord blood stem cells for use in regenerative medicine. Expert Opinion on Biological Therapy. 2007;7(9):1311-1322.

2. U.S. National Library of Medicine and National Institutes of Health. Medline Plus. Congenital Heart Disease page. Accessed January 2008.

3. National Institutes of Health. Stem Cell Information Page. Accessed January 2008.

4. Ma N, Stamm C, Kaminski A, Li W, et al. Human cord blood cells induce angiogenesis following myocardial infarction in NOD/scid-mice.Cardiovascular Research. 2005;66(1):45-54.

5. Hu CH, Wu GF, Wang XO et al. Transplanted human umbilical cord blood mononuclear cells improve left ventricular function through angiogenesis in myocardial infarction. Chin Med J (Engl). 2006;119(18):1499-506.

6. Ma N. Ladilov Y, Kaminski A, Piechaczek C. Stamm C. Umbilical cord blood cell transplantation for myocardial regeneration. Transplant proc. 2005;38(3):771-3.

7. Leor J, Guetta E, Feinberg MS et al. Human umbilical cord blood-derived CD133+ cells enhance function and repair of the infarcted myocardium. Stem Cells. 2006;24(3):772-80.

8. Henning RJ, Abu-Ali H, Balis JU, Morgan MB, Willing AE, Sanberg PR. Human umbilical cord blood mononuclear cells for the treatment of acute myocardial infarction. Cell Transplant. 2004;13(7-8):729-39.

9. Cheng F, Zou P, Handong Y. Induced differentiation of human cord blood mesenchymal stem/progenitor cells into cardiomyocyte-like cells in vitro. J Huazong Univ Sci and Tech. 2003;23(2):154-157.

10. Nishiyama N, Miyoshi S, Hida N, et al. The significant cardiomyogenic potential of human umbilical cord blood-derived mesenchymal stem cells in vitro. Stem Cells. 2007;25(8):2017-24.

11. Bonanno G, Mariotti A, Procoli A, et al. Human cord blood CD133+ cells immunoselected by a clinical-grade apparatus differentiate in vitro into endothelial- and cardiomyocyte-like cells. Transfusion. 2007;47(2):280-9.

12. Yamada Y, Yokoyama S, Fukuda N, et al. A novel approach for myocardial regeneration with educated cord blood cells cocultured with cells from brown adipose tissue. Biochem Biophys Res Commun. 2007;353(1):182-8.

13. Schmidt D, Breymann C, Weber A, Guenter CI, Neuenschwander S, Zund G, Turina M, Hoerstrup SP. Umbilical cord blood derived endothelial progenitor cells for tissue engineering of vascular grafts. Ann Thorac Surg. 2004 Dec;78(6):2094-8.

14. U.S. National Library of Medicine and National Institutes of Health. Medline Plus. Peripheral Vascular Disease page. http://www.nlm.nih.gov/medlineplus/peripheralvasculardiseases.html. Accessed January 2008.

15. Ikeda Y, Noboru F, Wada M, Matsumoto T, Satomi A, Yokoyama SI, Saito S, Masumoto K, Katsuo K, Mugishima H. Development of angiogenic cell and gene therapy by transplantation of umbilical cord blood with vascular endothelial growth factor gene. Hypertens Res. 2004;27(2):119-128.

16 Cho S-W, Gwak S-J, Kang S-W, et al. Enhancement of angiogenic efficacy of human cord blood cell transplantation. Tissue Eng. 2006;12(6):1651-1661.

Multiple Sclerosis, with an incidence of 100 in 100000 in the US and Europe, is by far the most frequent neurodegenerative disease (1). MS is a chronic, demyelinating disease of the brain and spinal cord - collectively the central nervous system (CNS). Demyelination is a process of gradual destruction of the myelin sheath, that surrounds many of the axons of nerve cells (neurons), leading to axonal injury or loss and consequently severely impaired nerve signals. The disease is named for the multiple scleroses (scars or plaques) that are created on the myelinated axons. A repair mechanism - remyelination of the axons by cells known as oligodendrocytes - takes place in the early phases of disease but the reformed myelin sheaths are thinner and less effective. Repeated attacks lead to fewer effective remyelinations until a scar is built up on the damaged axon. The central nervous system should be able to recruit oligodendrocyte stem cells but something would seem to inhibit stem cells in the affected areas.

Electron micrograph showing branched oligodendrocytes with processes extending to several underlying axons

One oligodendrocyte wraps myelin around axons of several neurons

It is generally accepted that MS is an inflammatory autoimmune disease - whereby an individual’s own immune response attacks the nervous system. Certain viruses, bacteria, stress and genetics have been implicated in disease manifestations. MS causes a variety of symptoms depending on where in the CNS the multiple lesions occur. Also, neurological deficits are progressively accumulated. In any individual there may be several complicating factors affecting the unpredictable course of the disease - there may be times of dormancy or times when there is steady progression.

The disease is categorised by several subtypes:
Relapsing remitting MS: unpredictable relapses (attacks) followed by months to years of remission. Effects of attacks may either resolve or may be permanent.
Secondary progressive MS: characterised by neurologic decline between attacks without periods of remission. Most common type of MS and causes most disability.
Primary progressive MS: decline occurs continuously without clear attacks, no remission.
Progressive relapsing MS: steady neurologic decline from onset, patients suffer superimposed attacks. Least common.

While MS does not currently have a cure, there are several treatments available for moderating the symptoms and for managing the various consequences of attacks. The currently approved treatments are aimed at returning function after an attack and preventing disability.

MS Treatment Objectives - the way forward: A Role for Stem Cells

During multiple relapses in the course of MS, oligodendrocytes and their progenitors are lost(2) and the nervous system has only limited capacity to recover from this extensive neuronal or glial damage. This is partly due to the formation of barriers, known as "glial" scars, which are triggered by the body to protect the injured nerve tissue from further injury. This dense scar tissue throws up a blockade to foreign cells, including transplants meant to heal and regenerate (group at Harvard medical school). There is evidence, however, that the adult CNS retains populations of cells with stem cell-like properties that have extensive proliferative capacity (3).

The challenge for current medical therapies appears to be remyelinating chronically demyelinated axons. Two distinct approaches can be considered to promote myelin repair; in one the endogenous myelin repair processes are stimulated through the delivery of growth factors, and in the second the repair process are augmented through the delivery of exogenous cells with myelination potential. Also, the effective treatment of MS requires modulation of the immune system, since demyelination is associated with specific immunological activation (4).

Karussis and kassis (sept 2007) described how different stem cells migrate to areas of white matter lesions (plaques) and have the potential to support local neurogenesis and rebuilding of the affected myelin – believed to be achieved by support of the resident CNS stem cells and by differentiation of the transplanted cells into neurons and myelin-producing oligodendrocytes. These stem cells were also shown to possess immunomodulating properties.

Several types of stem cells (discussed later in this article) having the capacity for promoting myelin repair, as well as modulating the immune response, are potential candidates for MS therapy.

Stem cell transplantation for treating MS: current developments (as at 2007)

Many inflammatory diseases are diffuse and widespread. However, intravenous injection has been demonstrated as an appropriate means of diffuse delivery of stem cells with the possibility of targeting; the problem for distribution to other tissues or organs still needs evaluation (1,5).

Neural stem cells: Many different cell types, including neural stem cells and precursors, have been suggested as candidate cells for therapy. There are however complexities in obtaining neural stem cells from the adult CNS. A group from the University of California, San Francisco published their findings in The Scientist (July 2007) cautioning against the notion that neural stem cells can generate any type of neuron. This group predict difficulties in using adult neural stem cells to treat neurological disease, although it remains possible that scientists could manipulate neural stem cells in vitro to make them more flexible.

Bone marrow stem cells: As early as the year 2000 adult bone marrow cells were shown to have the capacity to differentiate to oligodendroglial cells indicating their potential for treating demyelinating diseases (6). At the same time, a phase II trial using autologous bone marrow stem cell transplantation to treat 85 patients for progressive MS was conducted in 20 European centers. Neurological improvement was seen in 21% of patients; confirmed progression-free survival was seen in 74% of patients at 3 years; disease progression occurred in 20%. Additionally, it was reported that autologous haematopoietic stem cell transplantation can regenerate a tolerant immune system and is a potentially effective rescue therapy in a subset of patients with aggressive forms of MS refractory to approved immunomodulatory and immunosuppressive agents (7). Cassiani-Ingoni and fellow investigators, suggest that bone marrow transplantation can suppress inflammatory disease in a majority of MS patients, but retards clinical progression only in patients treated in the early stages of the disease (8).

Mesenchymal stem cells (MSCs): [Mesenchymal cells are non-haematopoieic stem cells derived from marrow or umbilical cord, the more appropriate terminology is multipotent stromal cell yet MSC still persists in the literature] Emerging evidence suggests that mesenchymal stem cells may have the capacity to generate cells with the characteristics of neurons and glia and consequently promote repair in the injured CNS. How mesenchymal stem cells affect functional recovery in the damaged adult CNS is not well understood. Possibly the transplanted multipotent cells migrate to the injury sites, proliferate, and then differentiate into the appropriate neural cells that then effect repair. Although mesenchymal stem cells have a high survival and migration potential, the proportion that can be directed towards a neural fate appears to be relatively small. It may be that MSCs, through the release of soluble signals in areas of injury, have a direct influence on the endogenous neural stem cells to promote repair through neuro- and oligodendrogenesis (3).

Mesenchymal cells can also exert immunomodulatory effects by inducing suppression of the autoimmune myelin-targeting lymphocytes. MSCs harvested from bone marrow can be obtained from the donor patient him/herself, thereby reducing the risk for developing malignancies. It has been mooted that these cells offer significant practical advantages over other types of stem cells (5,9).

CD34+ cells: CD34+ cells are multipotent haematopoietic stem cell found in bone marrow and umbilical cord blood. These stem cells are reportedly capable of transforming into neuroprotective glia and myelin-producing oligodendrocytes (10). A proposed advantage of umbilical cord CD34+ stem cell transplantation is that, when adminstered without additional medications and powerful immune suppressants, virtually no side effects are evident (10).

Stem Cell Therapy – cause for optimism
Significant advances have been made in researching the therapeutic potential of stem cells for neurodegenerative diseases and there are already several facilities offering stem cell treatments! Transplanting cells into focal MS lesions may be the ultimate therapeutic approach, and clinical trials may be the way to determine whether exogenous stem cells are able to survive, differentiate and myelinate axons in plaques(2). While the current number of stem cell-based clinical trials for demyelinating diseases is limited, this is likely to increase significantly in the next few years (4).

References

1. Magnus, Rao et al. Neural stem cells in inflammatory CNS diseases: mechanisms and therapy J. Cell. Mol. Med. (2005) 9:2 303-319
2. Duncan I Replacing cells in multiple sclerosis J.Neurol.Sci. Jun 2007 (epub ahead of print)
3. Bai, Caplan, Lennon & Miller Human Mesenchymal Stem Cells Signals Regulate Neural Stem Cell Fate Neurochem Res (2007) 32:353–362
4. Miller & Bai. Cellular approaches for stimulating CNS remyelination Regenerative medicine 2007 Sept 2 (5) 817-829
5. Karussis, Kassis, Basan, Slavin. Immunomodulation and neuroprotection with mesenchymal bone marrow stem cells: a proposed treatment for MS J.Neurol.Sci 2007 July (epub ahead of print)
6. Bonilla, Alarcon, Villaverde et al Eur J Neurosci 2002 15(3) 575-582.
7. Muraro, Bielekova Emerging therapies for MS,. Neurotherapeutics 2007 Oct 4(4) 676-692
8. Cassiani-Ingoni, Muraro, Magnus et al. Disease progression in a model of MS J.Neuropathol Exp Neurol 2007 Jul 66(7);637-49
9. Karussis & Kassis. Use of stem cells for the treatment of MS Expert Review of eurotherapeutics 2007Sept: 7(9) 1189-1201
10. Steenblock, D - www.stemcelltherapies.org electron micrograph from http://neurophilosophy.wordpress.com

Damage and Disability caused by Stroke
At present, ischaemic stroke is the third leading cause of death in industrialised countries. With an annual incidence of 250–400 in 100 000 inhabitants, around 1 million people suffer from a stroke each year in the United States and in the European Union(1). Approximately a third of cases are left with some form of permanent impairment, making stroke the single largest cause of severe disability in the developed world. This leads to a huge social and economic burden.

Stroke is caused by the interruption of blood flow in a brain-supplying artery; commonly an embolus causes an occlusion (blockage) in the blood vessel. Ischaemic stroke (cerebral infarction) and the even more devastating intracerebral haemorrhage, cause a disturbance of neuronal circuitry and disruption of the blood-brain-barrier that can lead to functional disabilities – very typically destroying a person's ability to speak and move normally. At this time, therapy is primarily based on the prevention of recurrent (secondary) strokes. Rehabilitation therapy is important for maximizing functional recovery in the early phase after stroke, but once recovery has plateaued there is no known treatment. There are still no neuroprotective therapies available that reduce brain damage and improve neurological recovery once a stroke has occurred(2).

Stem cell treatment could be the major breakthrough in effecting repair of some of the damage caused by stroke.

Cell transplantation in experimental models of stroke
Research: 2001-2008
Recent studies have highlighted the enormous potential of cell transplantation therapy for stroke. A variety of cell types derived from humans have been tested in experimental/rodent stroke models. Human cells that have been used in these studies belong in three categories: (i) neural stem cells cultured from foetal tissue; (ii) immortalised neural cell lines; and (iii) haematopoietic/endothelial progenitors and stromal cells isolated from bone marrow, umbilical cord blood or peripheral blood(3).

While human embryonic stem cells offer a virtually unlimited source of neural cells for structural repair in neurological disorders such as stroke, there are the ethical and safety concerns.Adult neural progenitor cells can be obtained from different tissues, can be safely expanded in vitro, and have shown promising therapeutic effects in several neurological disorders without causing serious side effects(2).

The purpose of this review is to focus specifically on the prospects of umbilical cord blood cells as stroke therapy.

Review of human umbilical cord blood cell (HUCBC) treatments for stroke:

As early as 2001, a study was conducted to assess whether an intravenous infusion of human umbilical cord blood cells in a rodent model, could enter the brain, survive, differentiate, and improve neurological functional recovery at 24 hours and 7 days after stroke. The study objectives were all achieved to a certain extent(4).

In 2005 a research team at the University of South Florida investigated strategies to effectively treat stroke patients other than by re-canalisation of the occluded vessels in the cerebral infarcted area. This group also investigated strategies to extend the narrow anticoagulant treatment window to which only a minority of patients have timely access. The following results were published: rats receiving human cord blood cells 24 h after stroke demonstrated improvements in behavioural defects; the 3 hour therapeutic window for anticoagulant treatment of stroke victims may be extended 24-72 hours post stroke with the use of umbilical cord blood cell therapy(5).

Paradoxically, a Finnish study (2006) reported that human cord blood cells, administered intravenously 24 h after stroke in rats, did not improve functional sensorimotor and cognitive recovery because of limited migration of cells(6), but that an infusion of pure CD34+ cells following focal cerebral ischemia demonstrated some improvement in functional outcome(7).

Recently, Kim et al(8) showed that human mesenchymal (CD34+) stem cells transplanted intravenously (ipsi- and contralateral) into a rat after ischaemic stroke, possessed the capacity to migrate extensively to the infarcted area. Promising data were also recently cited for treatment of intracerebral haemorrhage (ICH): intravenous delivery of cord blood cells might well enhance endogenous repair mechanisms and functional recovery after ICH(9, 10).

Current knowledge supports HUCBC as cell transplant candidate for stroke:

It goes without saying that the ideal cell for transplantation should meet all the criteria of safety for the receiver as well as offer the highest therapeutic potential. Therapeutic preparations for stroke require an adequate cell number, which raises the need to expand the precursor cell source in vitro (cell culture).

• Cord blood is composed of many cell types including haematopoietic and endothelial stem/progenitor cells (CD34-), mesenchymal cells (CD34+), immature lymphocytes and monocytes. It is not clear which of these cells are important for functional recovery after stroke.
• Umbilical cord blood cells, whether delivered intracerebrally or intravenously, target the ischaemic border. Chemokines - induced by injury - are thought to mediate this migration process.
• Few transplanted cells are found in the brain, even when delivered intracerebrally. Given the controversy of whether these cells can really become neurons, it is unlikely that they act to replace the damaged tissue; it is more feasible that they secrete factors that enhance inherent brain repair mechanisms(11).

Evidence(review.3) suggests that transplanted cells may work in the following ways:

• increase vascularisation: Increased blood flow in the ischaemic area within a few days after stroke is associated with neurological recovery. The induction of new blood vessel formation (angiogenesis) has been reported with transplantation of several stem cells including those from human cord blood.
• enhance endogenous (inherent) repair mechanisms. Human cord blood cells in the ischaemic cortex increased sprouting of nerve fibres.
• reduce death of host cells. Several cell types elicit a neuroprotective effect whereby, presumably by the secretion of trophic factors, there is often reduction in lesion size and inhibition of cell death.
• reduce inflammation. It has been reported that stem cells can directly inhibit T-cell activation, thus inhibiting the immune response. Intravenous injection of human umbilical cord blood cells reduced leukocyte infiltration into the brain thereby reducing the stroke-induced inflammatory/immune response.

Clinical Trials

Results: As a consequence of the encouraging results from experimental studies, pre-clinical phase I and II trials, using different types of stem cells, were tested in patients suffering from stroke (see Table 1 below). Although some of these trials could demonstrate neurological improvements and cell transplantations appeared to be a safe procedure, the precise mechanisms underlying the restorative effects of stem cells were poorly known at the time of trial(2).

Table 1. Cell-based therapies tested in pre-clinical trials (Baciguluppi et al., 2008)


Click here to enlarge this table

NT2/D1 cells are from a human embryonic carcinoma–derived cell line and have the capacity to develop into diverse mature nerve-like cells (LBS neurons; Layton BioScience Inc.) When transplanted, these neuronal cells survived, extended processes, expressed neurotransmitters, formed functional synapses, and integrated with the host. Safety and feasibility of cellular repair were achieved in this setting. Although this small study was not powered to demonstrate efficacy, valuable data will help in the design of subsequent clinical trials(3).

Future clinical trials considerations: It has been widely proposed that further research should focus on the development of new cell lines; on refining clinical inclusion criteria; on evaluating the need for immunosuppression; and an evaluation of whether ischemic stroke may be more suited to cell therapy than haemorrhagic stroke.

• CTX0E03, a human neural stem cell line, has been developed (by ReNeuron Group) for the treatment of stable ischaemic stroke. The cell line has been tested in rodent stroke models and in normal nonhuman primates. An application for a Phase I clinical trial, running for 24 months, has been submitted to the US Food and Drug Administration(reported in 1).

• Human umbilical cord blood cells: The use of HUCBC for traumatic brain injury in children has just been approved (ClinicalTrials.gov Identifier: NCT00254722). This is the first clinical trial using these cells for a neurological disorder(reported in 3).

• Timing of transplantation: The brain environment changes dramatically over time after ischaemia. The optimal time to transplantation after a stroke will depend on the cell type used and their mechanism of action. If a treatment strategy focuses on neuroprotective mechanisms, acute delivery of the cells will be critical; if the cells act to enhance repair mechanisms (e.g. angiogenesis) then early delivery would be pertinent because these events are most prevalent in the first 2 to 3 weeks after ischemia; if cell survival is important, then transplanting late, after inflammation has subsided, could be beneficial(3).


• Lesion location and size While experimental data suggest that recovery from cortical damage may be more complex than from striatal damage, a conclusive statement can not be made at this point. Precise anatomic location of the lesion and its functional implication, as well as lesion size, will be critical determinants to define the target patient populations for transplantation therapy clinical trials.

Conclusions
WCell transplantation therapy for stroke holds great promise. However, many fundamental questions related to the optimal candidate (including the patient age, anatomic location and size of the infarct, and medical history), the best cell type, the number and concentration of cells, the timing of surgery, the route and site of delivery, and the need for immunosuppression remain to be answered. Longer-term studies are required to determine whether the cell-enhanced recovery is sustained. Other challenges include ensuring appropriate manufacturing, and quality control of transplanted cells. Clearly, more research is needed to translate cell transplantation therapy to the clinic in a timely but safe and effective manner so that the remarkable potential already shown for cell transplantation to aid recovery from experimental stroke can become a reality for the patient(3).

REFERENCES
1. Stroke repair with cell transplantation: neuronal cells, neuroprogenitor cells, and stem cells Kondziolka D, Wechsler L. Neurosurg Focus. 2008; 24 (3-4):E13.

2 Neural stem cells for the treatment of ischemic stroke Bacigaluppi M, et al. Journal of the Neurological Sciences 265 (2008) 73–77

3. Cell Transplantation Therapy for Stroke Bliss T, Guzman R, Daadi M; Steinberg G. Stroke. 2007; 38[2]: 817-826.

4. Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Chen J, et al. Stroke. 2001; 32 (11):2682-8

5. Stroke-induced migration of human umbilical cord blood cells Newman M, et al. Stem Cells Dev. 2005 Oct;14(5):576-86.

6. Human umbilical cord blood cells do not improve sensorimotor or cognitive outcome following cerebral artery occlusion in rats. Mäkinen S, Kekarainen T, Nystedt J, et al.. Brain Res. 2006 Dec 6; 1123 (1):207-15.

7. Human cord blood CD34+ cells and behavioral recovery following focal cerebral ischemia. Nystedt J, Mäkinen S, et al. Acta Neurobiol Exp. 2006; 66 (4):293-300

8. In vivo tracking of human mesenchymal stem cells in experimental stroke. Kim D, et al. Cell Transplant. 2008; 16(10):1007-12.

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11. Growth factors, stem cells, and stroke Kalluri H, Dempsey R. Neurosurg Focus. 2008; 24(3-4):E14.