Developing Stem Cells Therapeutics For Parkinson’s Disease: Is Induced Pluripotent Stem Cells The Silver Bullets In Comparison to Other Stem Cells?
Stem cells have been researched to be therapeutic tools for neurodegenerative disorders, based on their potential to give rise to the appropriately re-engineered cell types after grafting in vivo. In this review I summarize some of the evidence currently available concerning the potent effect of Induced Pluripotent Stem Cells compared to Embryonic Stem Cells and Adult Tissue-Specific Stem Cells approaches for the treatment of Parkinson’s disease: (1) The similarities and differences between embryonic stem cells, adult specific stem cells, and induced pluripotent stem cells for cell replacement therapy. (2) The review of the future of stem cells therapy in the approach to the treatment of Parkinson’s disease.
What Are Stem Cells?
Stem cells are a uniquely reusable source of tissue that can be re-engineered to become different cell types of the body. The simplest examples are the embryonic stem (ES) cells found within an early-stage embryo. These cells can generate all the major cell types of the body before they matured into adult cell types. These cells are able to change or differentiate into other cell types.
A stem cell line is a group of cells that all originate from a single original stem cell and is grown in a laboratory; they keep on growing but don’t differentiate into specialized cells. They ideally remain free of genetic defects and continue to create more stem cells for regeneration and growth.
Why Stem Cell Therapy?
Stem cells remains at the center of a new field of science called Cell Regenerative Medicine enabling growing of stem cells with potentials to be re-engineered to become cartilage, muscle, neurons, bone, and other specialized types of cells. This and other sundry qualities make them have the potential to treat many diseases, including Parkinson’s, Alzheimer’s, Diabetes, Stroke, Spinal Cord Injury, Multiple Sclerosis etc.
Stem cell therapy is a modern intervention strategy for introduction of new adult stem cells into damaged tissue in order to treat disease or injury. Many medical researchers believe that stem cell treatments have the potential to change the face of intractable human diseases and alleviate suffering of those that are undergoing pains and terminal diseases. The ability of stem cells to renew themselves and give rise to future generations with variable degrees of differentiation potentials, offers significant capacities for generation of tissues that can potentially replace diseases and damaged areas in the body, with minimal risk of persistent rejection and side effects.
Types of Stem Cells:
- Embryonic Stem Cells
Embryonic stem cells are obtained from the inner cell mass of the blastocyst, which is an early embryonic developed thin-walled hollow structure containing a cluster of cells called the inner cell mass from which the embryo arises three to five days after an egg cell is fertilized by a sperm.
In normal early embryonic development, the cells inside the blastocyst divide for a short time, afterwards start to develop into more specialized cells giving rise to the entire body containing all of our tissues and organs. Modern scientists now have the ability to extract the inner cell mass and grow these in the laboratory. These are called embryonic stem cells, and when grown under the right conditions, can grow indefinitely in the laboratory.
When you say embryonic stem cells are pluripotent, it means they can give rise to every cell type in the fully formed body, and these cells are incredibly valuable because they provide a renewable resource for studying normal development and disease, and for testing drugs and other therapies.
2. Adult Tissue-specific stem cells
Adult Tissue-Specific Stem Cells are more specialized than embryonic stem cells with potentials to generate different cell types for the specific tissue or organ in which they live. They are also referred to as somatic or adult stem cells.
For example, hematopoietic or blood-forming stem cells in the bone marrow can give rise to red blood cells, white blood cells and platelets. In the contrary, hematopoietic stem cells don’t generate liver or lung or brain cells, and stem cells in other tissues and organs don’t generate platelets, white blood cells or red blood cells.
Some tissues and organs within human body contain small stores of tissue-specific stem cells whose job it is to replace cells from that tissue that are lost during activities of daily living or when injury occurs, for example those in your skin, blood, and the lining of the gut.
Tissue-specific stem cells apart from being difficult to find in the human body don’t also seem to self-renew in culture as easily as embryonic stem cells. However, study of these cells has made increase in our general knowledge about normal development, changes in aging, and what happens when there is injury and disease.
3.Induced Pluripotent Stem Cells
Induced Pluripotent Stem (iPS) Cells are cells that have been re-engineered in the laboratory to appear like embryonic stem cells. IPS cells are critical tools to help scientists learn more about normal human development, disease onset and progression, with additional ability for developing and testing new drugs and therapies.
It is important to state that though iPS cells share many of the same characteristics of embryonic stem cells, including the ability to give rise to all the cell types in the body, they aren’t actually the same. Scientists are exploring what these differences are and what they mean.
To move forward with this we need to understand that the first iPS cells were produced by using viruses to insert extra copies of genes into tissue-specific cells with profound success and outlook into the strange world of stem cells.
With this grand exploration, modern researchers are experimenting with many alternative ways of creating iPS Cells so that they can ultimately be used as a source of cells or tissues for medical treatments.
What are the similarities and differences between embryonic and adult stem cells?
Human embryonic and adult stem cells each have advantages and disadvantages if we need to understand in clear terms their potential uses for cell-based regenerative therapies.
One major difference between adult and embryonic stem cells is their distinct different abilities in the number and type of differentiated cell types they can become.
Embryonic Stem Cells can become all cell types of the body because they are also pluripotent or able to differentiate into different cell types no matter their origin but adult stem cells are known to be limited to differentiating into different cell types of their tissue of origin.
Embryonic stem cells can relatively and easily be grown in culture. Its challenging to isolate Adult stem cells which are rare in mature tissues, and methods to expand their numbers in cell culture have not yet been worked out. It is note-worthy to state that large numbers of cells are needed for stem cell replacement therapies which; an important distinction when you compare the two.
Scientists believe that tissues derived from embryonic and adult stem cells may differ in the likelihood of being rejected after transplantation. We don’t really know for certain if tissues derived from embryonic stem cells would cause transplant rejection, since relatively few clinical trials have commenced testing the safety of transplanted cells derived from human Embryonic Stem Cells.
Adult stem cells and its tissue derivations are currently believed less likely to initiate rejection after transplantation because a patient’s own cells could be expanded in culture, re-engineered into assuming a specific cell type (differentiation), and then reintroduced into the patient.
The use of adult stem cells and tissues derived from the patient’s own adult stem cells would mean that the cells are less likely to be rejected by the immune system. This represents a significant advantage, as immune rejection can be circumvented only by continuous administration of immunosuppressive drugs, and the drugs themselves may cause serious side effects.
How does Induced Pluripotent Stem Cells affect treatment of Parkinson’s Disease?
Induced pluripotent stem (iPS) cells discovered in 2007 in addition to ES represent of one the important developments in stem cell research efforts to treat debilitating diseases like Parkinson’s disease. It’s also important to note that iPS cells are ‘man-made’ stem cells that share ES cells’ ability to become other cell types. IPS cells are created when scientists reprogram a mature cell, such as a human skin cell, into an embryonic-like state. These cells may have potential both for cell replacement treatment approaches in patients and as disease models that scientists could use in screening new drugs.
Induced pluripotent stem cell technology is related to a previous method called somatic cell nuclear transfer (SCNT) or the technology that gave us Dolly the Sheep otherwise called therapeutic cloning.
The iPS cell approach converts adult cells directly into stem cells in contrast to SCNT which involves transferring the genetic material of an adult cell into an unfertilized human egg cell, allowing the egg cell to form an early-stage embryo and then collecting its ES cells which are now genetic “clones” of the person who donated the adult cell. To date, however, this has not been successfully demonstrated with human cells and iPS cell methods may be replacing SCNT as a more viable option.
Modern Researchers lately have identified a potential and exciting use for iPS cells in the development of cell models of Parkinson’s disease. In theory, scientists could use cells from people living with Parkinson’s disease to create iPS cell models of the disease that have the same intrinsic cellular machinery of a Parkinson’s patient. Researchers could use these cell models to evaluate genetic and environmental factors implicated in Parkinson’s disease.
With the considerable progress that have been made in creating dopamine-producing cells from stem cells, stem cell research has the potential to significantly impact the development of disease-modifying treatments for Parkinson’s disease. Cell models of Parkinson’s disease generated from stem cells could help researchers screen drugs more efficiently than in currently available animal models, and study the underlying biological mechanisms associated with Parkinson’s disease in cells taken from people living with the disease.
The development of new cell models of Parkinson’s disease is a revolutionary and promising area of stem cell research, as the current lack of progressive, predictive models of Parkinson’s disease remains a major barrier to drug development and adjunct therapy.
In a major breakthrough for the treatment of Parkinson’s disease published on the 6th of November, 2014 in Lund University in Sweden web site, researchers working with laboratory rats show it is possible to make human embryonic stem cells to produce a new generation of dopamine cells that behave like natural dopamine cells when transplanted into the brain of rats replacing the cells lost to the disease.
Malin Parmar an associate Professor in Lund’s Department of Medicine, who led the revolutionary study conducted at Lund University and at MIRCen in Paris as part of the EU networks NeuroStemCell and NeuroStemcellRepair says that-
“The experiments, performed in rat models of Parkinson’s disease, reveal that the latest version of stem cell-derived dopamine cells fully mimic the characteristics and function of the dopamine neurons that are lost in Parkinson’s disease. The potentially unlimited supply of transplantable cells, sourced from stem cell lines, opens the door to clinical application on a much broader scale. The results are published in the leading journal in the field, Cell Stem Cell.
“This study shows that we can now produce fully functioning dopamine neurons from stem cells. These cells have the same ability as the brain’s normal dopamine cells to not only reach but also to connect to their target area over longer distances. This has been our goal for some time, and the next step is to produce the same cells under the necessary regulations for human use. Our hope is that they are ready for clinical studies in about three years”.
The effects of stem cell therapy on Parkinson’s disease signs and symptoms?
Patients who undergo stem cell therapy may report improvements in one of more disease related complications such as:
- Primary Motor Symptoms
- Resting Tremor:- Shaking or slight tremor in the hand or foot on one side of the body, the jaw or face and usually appears when a person’s muscles are relaxed, not performing an action or at rest.
- Bradykinesia:- Slow movement or a general reduction of spontaneous movement, which can give the appearance of a sudden stop during movement and a decrease in facial expressivity. This can cause difficulty with repetitive movements and performing activities of daily living, such as wearing clothes, cutting food, body grooming, and mostly resulting to walking with short, shuffling gaits, and also speech defects; quieter and less distinct, drooling and excess saliva result from reduced swallowing movements.
- Rigidity:- Rigidity causes stiffness and lack of flexibility of the limbs, neck and trunk. The muscle tone of an affected limb is always stiff and does not relax, which sometimes can contribute to spasticity or a decreased range of motion. Rigidity can be uncomfortable or even painful and inhibit arms movement when walking.
- Postural Instability:- Postural Instability is caused by uncontrollable reflexes needed for maintaining an upright posture that can cause particular difficulty in postural stability when walking or when pivoting or making turns or quick movements.
- Secondary Motor Symptoms
- Freezing– Sudden stop in movement or freezing of gait with hesitation before stepping forward is a manifestation of what is called akinesia (poverty of spontaneous movement). The feeling as if their feet are glued to the floor can increase a person’s risk of falling forward.
- Micrographia- shrinkage in handwriting occurs as a result of bradykinesia and hypokinesia which essentially refer to the fact that, in addition to being slow, the movements are also smaller than desired.
- Mask-like Facial Expression- Face appearing less expressive than usual is a manifestations of akinesia (poverty of spontaneous movement [e.g. in facial expression]).
- Dystonia- A neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures.
- Impaired fine motor dexterity and motor coordination- Encompass the abilities required to control the smaller muscles of the body for writing, playing an instrument, artistic expression, and craft work.
- Impaired gross motor coordination- Abilities required in controlling the large muscles of the body for ambulation and other forms of walking, running, sitting, and crawling.
- Dysphagia- Difficulty swallowing.
- Sexual dysfunction- Difficulty experienced during sexual activity, including physical pleasure, desire, preference, arousal or orgasm.
- Drooling- Sialorrhea (the flow of saliva outside the mouth).
- Nonmotor Symptoms– The most recognizable early symptoms which many researchers believe may precede motor symptoms when making a Parkinson’s diagnosis include:
- Anosmia- loss of sense of smell
- Dyschezia- constipation
- Parasomnia-a sleep disorder
- Mood disorders- Depression, bipolar disorder, dysthymic disorder and cyclothymic disorder.
- Orthostatic hypotension- Sudden fall in blood pressure upon standing
- Other Nonmotor Symptoms may be presented in forms of excessive saliva, weight loss, weight gain, vision problems, dental problems, fatigue, depression, fear and anxiety, confusion, dementia, skin problems cognitive issues, sleep disturbances, bladder problems, and sexual problems.
We know that induced Pluripotent Stem Cells are adult cells that have been genetically reprogrammed to an embryonic stem cell–like state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells.
If scientists find drugs that treat the Parkinson’s disease in a lab dish, they will then test those same drugs in animals and develop the most promising into a therapy for people with the disease especially when they are able to create dopamine-producing cells in the lab dish with the hope that they could replace the neurons that are damaged in people with the disease.
Modern important stem cell research is a key step along the way in helping us to understand how stem cells might shape future Parkinson’s treatments especially when we begin to see the important potential advantages of the Induced Pluripotent Stem Cells over the fetal-derived Embryonic Stem Cells used in past cell transplantation work.
We are aware that varying results have been seen in brain cell transplants performed on few occasions using fetal dopamine cells obtained from human embryos. In the past decade, TRANSEURO- the EU network has been working hard to get a new and improved trial underway with transplants performed in Lund, Sweden and Cambridge, UK battling hard to resolve multiple restrictions over ethical concern of harvesting tissues from aborted fetuses and the issue of availability of fetal cells which is often scarce.
The revolutionary collaborative efforts within EU networks NeuroStemcellRepair and TRANSEURO have put cell therapy on a faster track towards reaching patients and getting induced Pluripotent stem cells to become functioning dopamine neurons. The method of delivering them to a specific target, and learning how to get them to integrate in the brain, are all extremely complicated processes but achievable with the level of progress and determination shown with gradual break in restrictions and ethical concerns over stem cells harvest and transplant.
- Hwang WS,Ryu YJ, Park JH, et al. Evidence of a pluripotent human embryonic stem cell line derived from a cloned blastocyst. Science 2004;303:1669-1674
- Perrier AL,Tabar V, Barberi T, et al. Derivation of midbrain dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci U S A 2004;101:12543-12548
- Barberi T,Klivenyi P, Calingasan NY, et al. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol2003;21:1200-1207
- Other Source Information : Michael J Fox Organization, Wikipedia, National Institutes of Health, Euro Stem Cell Org