Existing stem cells in the adult brain stimulated by drug to repair brain damage in animal models of multiple sclerosis Dr. Eva Sirinathinghji
There has been a great deal of excitement over the recent discovery that stem cells (see Box) with the potential to multiply indefinitely and generate many other different kinds of cells can be created from ordinary skin cells (see  The Promise of Induced Pluripotent Stem Cells, SiS 50). These ‘induced pluripotent stem cells’ (iPS cells) could be used to repair damaged tissue. For example, they can be turned into the types of brain cells – cholinergic neurones – that are thought to die early on in Alzheimer’s disease .
Although iPS cells may be useful for modelling diseases, their potential for regenerative therapy, as with embryonic stem cells, is still limited. The dangers of tumour formation following transplantation, as well as the requirement for brain surgery, on top of the little evidence of success in animal and human studies, are some of the major concerns regarding stem cell therapies for brain diseases.
In contrast to the use of exogenous stem cells for brain repair, researchers at Edinburgh and Cambridge Universities in the UK reported earlier that naturally existing stem cells in the adult brain can be stimulated by a drug to repair damage in animal models of multiple sclerosis (MS) .
This proof-of-principle experiment suggest that there is little scientific advantage in deriving embryonic cells for tissue repair when naturally existing adult stem cells can do the job, with minimum intervention and without raising ethical concerns (see  No Case for Embryonic Stem Cells Research, and other articles in the series, SiS 25).
Since the first derivation of human embryonic stem (hES) cells in 1998 , stem cell therapies have been investigated for a wide range of medical conditions from heart disease, diabetes, spinal cord injury, retinal disorders, stroke, as well as neurodegenerative diseases including Parkinson’s, Huntington’s disease and MS. A great deal of research to date has focused on the use of embryonic stem cells derived from human embryos for regenerative repair; though clinical success has only been reported for using the patient’s own adult stem cells (see  Patient's Own Stem Cells Mend Heart, SiS 25).
More recently, however, research based on utilising endogenous brain stem cells (a person’s own cells) has gained ground. Such a strategy can avoid all ethical issues associated with deriving stem cells from embryos. It also avoids the scientific complications of using embryonic cells grown in long-term culture, where their full cellular identity and capacity to differentiate into different kinds of cells, migrate and functionally integrate into patients bodies is still limited or unknown. Embryonic stem cell cultures are also notoriously unstable, showing genetic imbalances over time, and also have potential to develop into tumours . Furthermore, stem cell transplantation can require serious surgical procedures that are risky and expensive. Surgery on the brain would be best avoided under any circumstances, considering it is the most complicated, as well as least understood organ in our body.
Stem cells (see  Why Clone Humans? (Human Cloning & the Stem Cell Debate), SiS 16)
Stem cells are special cells that can divide indefinitely and give rise to differentiated cells.
Embryonic stem cells are derived from early embryos, which, in humans, consist of around 50-150 cells. At this stage, the embryo is made up of the inner cell mass, where the embryonic stem cells reside, and the trophoblast, which encases the inner cell mass, and will ultimately develop into the placenta. The embryonic stem cells aroused strong interest within the scientific and medical communities due their unique characteristics. First, they are pluripotent, undifferentiated i.e. unspecialised cells, with the ability to differentiate into all the specialised cell types of the developed body. Second, under certain laboratory conditions, they have the ability to continuously proliferate, allowing a constant and unlimited supply of cells for research or clinical purposes. Most commonly, embryonic stem cell lines are derived from excess or unfit embryos that were generated by in vitro fertilization.
Adult stem cells are also unspecialised cells that reside in various tissues of the adult body. Such populations can be found in organs and tissues including the brain, liver, mammary gland, bone-marrow and adipose tissue. Adult stem cells were generally thought of as multipotent, in that they are able to differentiate into a variety of cell types of the tissue from which the stem cells originate, but not pluripotent like embryonic stem cells. For example, adult stem cells in the brain are termed neural stem cells, and were thought to be able to differentiate into all types of brain cells only, i.e. neurones as well as non-neuronal brain cells like astrocytes and oligodendrocytes. However, more recently it has been shown that adult stem cells possess the ability to ‘transdifferentiate’, or differentiate into cell types outside of their host tissue. For example, haematopoietic stem cells that reside in the bone marrow have been shown not only to differentiate into all blood cell types, but additionally can differentiate into most other cell types, including heart, brain, and muscle cells. The restricted differentiation potential of even differentiated adult cells is now also being challenged, with numerous experiments showing the ease with which skin cells can be turned directly into brain or heart cells by the transient introduction of just three or four genes in laboratory conditions. Such studies highlight the dynamic nature of our cells, and this flexibility makes the use of adult stem cells therapeutically appealing, not just due to this differentiation capacity, but also due to the avoidance of immune rejection when adult stem cells from ones’ own body are used for therapy.
Induced pluripotent stem cells are ordinary cells that are induced to become stem cells. They were discovered in 2006 and dealt with elsewhere .
MS is a complex, autoimmune disorder characterised by inflammation, and degeneration of nerve cells (neurones) in the nervous system . The disorder starts with the improper activation of the immune system, which goes on to attack a protein in myelin (sheaths of specialized cells that encapsulate the nerve cell processes). This attack leads to demyelination (destruction of the myelin coating) and subsequent damage to nerve cells. It manifests as a wide range of progressive symptoms affecting sensation, vision, cognitive capacity, and the autonomic system regulating heart rate, breathing, digestion, and other functions. Most patients suffer from what is described as a relapse-remission type of MS, where there is a slow accumulation of neurological damage over time. However, in around 50 percent of these patients, the recovery becomes impaired in later stages of the disease, resulting in a secondary and more severe phase, where damage becomes irreversible. A small minority of patients suffer from an unremitting course of disease progression right from the initial onset. There is currently no effective therapy, although drugs that regulate the immune system can alleviate or slow symptoms in some patients.
The myelin protein that is attacked by the immune system is secreted by oligodendrocytes, a type of brain cell whose principle function is the production of myelin that encapsulates neurones. The myelin sheath protects neurones, and more importantly, facilitates the conduction of nerve signals down their long processes. During early brain development oligodendrocytes are produced from neural stem cells. This process continues into adulthood, where resident stem cells in the brain are capable of producing all the major cell types in the brain: neurones, astrocytes and oligodendrocytes. The regenerated oligodendrocytes can therefore replace dying or malfunctioning oligodendrocytes during a life-time. For example, following instances of acute demyelination, stem cells have previously been shown to differentiate into oligodendrocytes, and restore the myelin coating of neurones, a process called remyelination. Indeed, analysis of post-mortem brains from people who suffered from MS shows that oligodendrocyte cells are present in damaged lesions, suggesting that they have migrated there to repair the demyelinated cells. Furthermore, substantial remyelination has been noted during early stages of MS, while at latter stages when symptoms become irreversible, remyelination of nerve cells becomes limited. This also correlates with impairment in the ability of neural stem cells to fully differentiate into mature oligodendrocyte cells at these later stages. Such observations have made the idea of stem cell therapy to replace dysfunctional oligodendrocytes an appealing strategy. This strategy relies on the regenerative potential of stem cells to replace damaged nerve cells, as opposed to current immunosuppressive treatments that can only block further attacks on myelin but are unable to reverse damaged lesions.
The work published by Robin Franklin and colleagues  showed that by giving a naturally existing molecule known as 9-cis-retinoic acid to animal models of demyelination, endogenous neural stem cells were triggered to differentiate and remyelinate damaged neurones. First, they looked closely into the molecular signature that takes place during the process of remyelination, using micro-array technology to see which genes are expressed on a genome-wide level. By looking at these patterns of genes that get switched on and off during the repair of demyelinated regions of the brain, they found that retinoic acid receptors (that bind retinoic acid) were among the most activated genes during the stages of oligodendrocyte differentiation from their precursor stem cells. Retinoic acid is a molecule that naturally exists in the body, and mediates cellular proliferation, differentiation and apoptosis (cell death). It has been successfully used in the clinic for treating other diseases such as acute promyelocytic leukemia for many years, avoiding the need for studies into its clinical safety.
The importance of retinoic acid receptor activation in oligodendrocyte differentiation was tested in cells as well as animal models with molecular, morphological (shape of cells) as well as histological (study of cellular anatomy) methods. This was done by the administration of 9-cis-retinoic acid, which is exactly the same as the naturally existing retinoic acid. In cell cultures, the researchers showed that it was able to successfully increase oligodendrocyte differentiation from stem cell precursor cells, and most importantly, the myelination of nerve cells, as shown by the increase in myelin thickness as well as abundance of the myelin protein called myelin basic protein. Administration of this drug to animal models of demyelination also successfully repaired damaged lesions of the brains, even in aged mice, where oligodendrocyte differentiation is less efficient. To further confirm the role of retinoic acid, the reverse of such experiments was also performed. Inhibition of retinoic acid signalling led to impairments in oligodendrocyte differentiation and myelination.
This is an exciting approach to regenerative repair, and could be applied to many different diseases, not just those affecting the brain. Work on heart disease has also made progress in this area, where a recent paper showing that haematopoietic stem cells produced in adult bone marrow, can be pharmacologically manipulated to repair heart tissue following myocardial infarction (heart attack) in mice . By giving a molecule to the mice that mobilised stem cells from the bone marrow into blood circulation, along with a drug to protect its degradation, the stem cells were able to successfully reach the heart. This work led to generation of new blood vessels, improved cardiac function, and increased survival, offering hope in treating one of the biggest killers in the world, safely and affordably.
Adult stem cells are showing greater and greater promise in providing a more ethical alternative to embryonic stem cells. With the discovery of more and more resident stem cells in various adult tissues, the future lies with being able to utilise these cells to perform the job that, ultimately, they are perfectly designed to do.
Article first published 31/03/11
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Chris Slabbekoorn Comment left 20th March 2015 11:11:46
Dealing with several issues due to deterioration of the brain stem. I need to attempt to repair.