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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 19  |  Issue : 1  |  Page : 3-8

Stem cell therapy role in neurodegenerative disorders


1 Department of Psychiatry, Konaseema Institute of Medical Sciences & Research Foundation, Amalapuram, Andhra Pradesh, India
2 Department of Pharmacy Practice, Vikas Institute of Pharmaceutical Sciences, Rajahmundry, East Godavari, Andhra Pradesh, India
3 Dr. NTR Vaidya Seva Trsust, Government of Andhra Pradesh, Guntur, Andhra Pradesh, India

Date of Web Publication26-Jun-2018

Correspondence Address:
Dr. Kattula Rao Vinay Rajan
Dr. NTR Vaidya Seva Trust, Government of Andhra Pradesh, Behind Hero Gautam's Hero Showroom, Chuttugunta, Guntur, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AMH.AMH_10_18

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  Abstract 


Cellular therapies represent a new frontier in the therapy of neurological diseases. Earlier, regeneration of neurons has been admitted as an impossible event. Thus, neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's disease, and multiple sclerosis), vascular events (e.g., stroke), and traumatic diseases (e.g., spinal cord injury) have been identified as incurable diseases. Later on, tissue reparative and regenerative potential of stem cell researches for these disorders drew attention of scientists to replacement therapy. Now, there are hundreds of current clinical and experimental regenerative treatment studies. One of the most popular therapies is cell transplantation. Transplanted neural stem/precursor cells protect the injured central nervous system using a variety of articulated mechanisms, a mode of action named ''therapeutic plasticity,” encompassing both bystander effects (immunomodulation and enhancement of endogenous repair mechanisms) and cell replacement. An extensive search was made using PubMed, Scopus, and Google Scholar using the following search terms: stem cells, neurodegenerative disorders, Alzheimer's disease, and stem cell therapy. In this review, we presented the possible benefits of stem cell therapy in neurodegenerative disorders.

Keywords: Alzheimer's disease, neurodegenerative disorders, neuronal precursor cells, Parkinson's disease, stem cells


How to cite this article:
Ravisankar P, Dhanavardhan K, Prathyusha K, Rajan KR. Stem cell therapy role in neurodegenerative disorders. Arch Ment Health 2018;19:3-8

How to cite this URL:
Ravisankar P, Dhanavardhan K, Prathyusha K, Rajan KR. Stem cell therapy role in neurodegenerative disorders. Arch Ment Health [serial online] 2018 [cited 2018 Sep 21];19:3-8. Available from: http://www.amhonline.org/text.asp?2018/19/1/3/235314




  Introduction Top


Stem cell-based therapies hold promise for the treatment of human illness. Each of the five sorts of human stem cells (embryonic, epithelial, biological process, neural, and mesenchymal [1]) has received appreciable attention from the scientific community for doubtless therapeutic properties. Stem cells are those cells that have the ability to continuously divide and differentiate into various other kinds of cells and tissues. There are three types of stem cells based on the differentiation potential; Totipotent cell has the power to create an organism alone, pluripotent cells can be converted into all cell types, and multipotent cells can be converted into cell types in their own tissues.[2] Neurons and interstitial tissue cells are generated from stem cells such as embryonic stem (ES) cells, elicited pluripotent stem cells, mesenchymal stem cells and neural stem (NS) cells.[3],[4] Thus, stem cell therapy might be beneficial in patients with neurodegenerative disorders.


  Results Top


Diagnostic knowledge confirmed that transplanted NS/neural precursor cells (NPCs) may exert a “bystander” neuroprotective impact and identified a series of molecules – for example, immunomodulatory substances, neurotrophic growth factors, stem cell regulators as well as guidance molecules – whose in-situ secretion by NPCs is temporally and spatially orchestrated by environmental needs. An improved understanding of the molecular and cellular mechanisms sustaining this “therapeutic plasticity” has its importance for outlining crucial aspects of the bench-to-beside translation of NS cell therapy.[5] Continued Phase I/II clinical trials will explore the safety and efficacy profile of the stem cells, while, on the other hand, new cellular sources are being developed by cellular reprogramming.[6]

Stem cell therapy in neurologic disorders

Neurologic diseases are caused by a loss of neurons and interstitial tissue cells within the central nervous system or peripheral nervous system.[7] Effective treatment of those neurologic diseases is presently not possible. Stem cell therapy may be a promising treatment possibility for these neurologic diseases.[8] To produce promising benefits and for clinical transplantation, stem cells should possess some essential properties such as the ability of clonal propagation in vitro to ensure homogeneity, genetic stability at high passage, integration within the host brain following transplantation, migration and engraftment at the sites of damage, and the lack of undesirable effects.[9],[10] The Significance of stem cell therapy in various neurodegenerative disorders is discussed below [Figure 1].
Figure 1: Pathways of various neurodegenerative diseases

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Stem cells – Huntington's disease

Huntington's disease (HD) may be a fatal, balky disorder that is characterized by chorea (excessive spontaneous movements) and progressive dementedness. It is caused by the death of neurons within the basal ganglion.[11] Stem cell therapy aims to preserve or restore brain function by acting at exchange and protective striatal neurons. Stem cell-based approaches are still in their infancy, and the reconstruction of striatal neural activity has not been observed in animals.[12] However, human neuronal stem cells deep rooted into the brains of rats were recently found to cut back motor impairments in experimental HD through trophic mechanisms.[13] At present, quite neuronic replacement, use of stem cells for the neuroprotection to stop disease progression, appears an additional realizable clinical goal in HD.[14]

Parkinson's disease

The hallmark of Parkinson's disease (PD) is gradual loss of nigrostriatal dopamine-containing neurons; however, degeneration additionally happens in systems of nondopaminergic neurons.[15] The most common symptoms are rigidity, poorness of movement (bradykinesia), tremor, and bodily property of instability. Current therapies focus on the oral administration of L-dopa, dopamine receptor agonists, and on deep-brain stimulation in the subthalamic nucleus. However, these treatments are effective for a few symptoms but are associated with side effects. They might not stop the progression of the disease.[16] To be clinically competitive, a stem cell-based therapy should be long, ameliorate classical symptoms, and counteract disease progression.[17] Clinical trials of the transplantation of human dopaminergic neurons have shown that cell replacement will deliver major long improvement in some patients.[18] This favors the use of stem cells with potency to regenerate dopaminergic neurons isolated from interstitial cells, bone marrow, and human brain.[19],[20] To make stem cell therapy work for PD,[21] dopaminergic neurons with the characteristics of neural structure must be produced in large numbers. For Dopaminergic neurons generated from human ES cells, survival after transplantation in animal models has been poor and needs to be markedly increased before clinical application. It will even be necessary to develop methods that hinder illness progression. One possible approach to prevent the death of existing neurons could be to transplant human stem cells engineered to express neuroprotective molecules such as glial-cell-line-derived neurotrophic factor (GDNF) [Figure 2].[22]
Figure 2: Stem cell transplant research – Parkinson's disease

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Amyotrophic lateral sclerosis

In amyotrophic lateral sclerosis (ALS), dysfunction and degeneration of motor neurons occur not only in the spinal cord (lower motor neurons) but also in the cerebral cortex and brain stem (upper motor neurons).[23] Muscle weakness progresses rapidly and death happens in a couple of years.[24] Stem cell therapy should restore or preserve the function of each higher and lower motor neuron, and new neurons should become integrated into the existing neural circuitries. Recent reports have shown its potential to get lower motor neurons in vitro from stem cells of assorted sources, as well as ES cells. Mouse ES cell-derived motor neurons establish purposeful synapses with muscle fibers in vitro and extend axons to ventral roots during transplantation into adult rats.[25] However, integration of these cells into the existing neural circuitries and restoration of motor function are not yet established;[26] whereas neuronic replacement in ALS patients seems a distant goal, using stem cells to stop motor neurons from degeneration may be an additional realistic and short-term clinical approach. This prospect is supported by studies showing that human embryonic germ cells delivered into the liquid body substance of rats with neuron injury will migrate into the funiculus and induce motor recovery, most likely through neuroprotection. The efficaciousness of this approach may well be improved by genetically modifying the stem cells to secrete molecules that promote neuron survival.[27] For instance, a study showed that human cortical progenitors that were engineered to express GDNF survived implantation into the spinal cords of ALS rats and released the neurotrophic factor.[28]

Stroke

Stroke is caused by blockage of artery, resulting in focal anemia; loss of neurons and interstitial tissue cells; and motor, sensory, or psychological feature impairments.[29] No effective treatment to promote recovery exists, so a therapy that produce even minor improvement would be valuable. Transplanted cells from different sources, such as fetal brain, neuroepithelial or teratocarcinoma cell lines, bone marrow and umbilical cord, have yielded some improvement in animals and, in one clinical trial, in humans affected with stroke.[30] In most cases, the grafts have acted by providing organic process factors that enhance cell survival and function. However, for stem cell therapy to be of major clinical worth, human cells ought to be able to replace dead neurons, remyelinate axons, and repair broken neural cells.[31] As a primary step toward this goal, human NS cells were transplanted into the brains of stroke-damaged rats, leading to the migration of latest neurons toward the ischemic lesion.[32] Other studies showed that monkey ES-cell-derived progenitors transplanted into the brains of mice after stroke differentiated into various types of neuron and glial cell, re-established connections with target areas, and led to improved motor function.[33] The therapeutic efficaciousness of such methods may well be improved more by genetically modifying the stem cells: as an example, by overexpressing associate-degree anti-apoptotic gene. Interestingly, the stroke-damaged adult placental brain has some capability for neuronic replacement from its own NS cells.[34] For several months after a stroke, NS cells will generate new striatal neurons that migrate to the location of damage. It is currently vital to ascertain whether or not endogenous maturation will contribute to purposeful recovery after stroke. Regeneration of animal tissue neurons is going to be the premise for purposeful improvement in most stroke-damaged brains. Effective therapies can rely on methods to extend the survival of the new neurons and to boost their incorporation into reorganizing neural circuitries.

Alzheimer's disease

Alzheimer's disease (AD) is characterized by neuronic and conjugation loss throughout the brain, involving the basal prosencephalon cholinergic system, amygdala, hippocampus, and several other animal tissue areas. Patients' memory and psychological feature performance is increasingly impaired; they develop dementia, and square measure seemingly to die untimely. Current therapies, such as treatment with acetylcholinesterase inhibitors to boost cholinergic function, offer solely partial and temporary alleviation of symptoms. The pathological changes seen in AD provide a particularly problematic scenario for cell replacement. Given the widespread and progressive injury within the brains of patients with AD, it is unlikely that the mechanisms for instructing transplanted NS cells to differentiate into new neurons are going to be intact. In theory, psychological feature decline caused by the degeneration of basal prosencephalon cholinergic neurons may well be prevented by the movement of cholinergic neurons generated from NS cells in vitro. But to provide long-lasting symptomatic benefit, this approach would require the existence of intact target cells within the patient's brain, and these are highly likely to be damaged. However, stem cells will be genetically changed and have migratory capability during transplantation; they might be used for the delivery of things that may modify the course of the illness. In support of this approach, basal prosencephalon grafts of fibroblasts produce nerve protein that counteracts cholinergic neuronic death, stimulate cell function, and improve memory in animal models [Figure 3].
Figure 3: Stem cell treatment for Alzheimer's disease

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Multiple sclerosis

Multiple sclerosis (MS) is caused by the inflammation-induced destruction of the sheath that surrounds axons, resulting in physical phenomenon deficits and a range of neurologic symptoms and, in some patients, major incapacity. Nerve fiber loss as a consequence of acute inflammation or chronic degenerative disorder is a vital reason for deterioration. Immunomodulatory treatment alone is not effective. Myelin-producing neuroglial ascendant cells are abundant in the adult human brain. Spontaneous remyelinating happens to varying degrees within the early stages of MS, and myelin-producing neuroglial ascendant cells can be a hope of choice in chronic demyelinated MS lesions. A vital space of analysis is that focused on finding ways to enhance remyelination from these cells and distinguishing the factors that cause a failure of cells to provide fat within the first place. To this end, one study [23] showed that astrocyte-derived hyaluronan accumulated in demyelinated lesions from MS patients and prevented the maturation of endogenous myelin-producing neuroglial ascendant cells. The transplantation of remyelinating cells represents another approach for treating fat loss in MS. Human adult and ES cell-derived myelin-producing neuroglial ascendant cells are shown to myelinate demyelinated mouse brain and funiculus during transplantation. However, a serious concern is that the inflammatory surroundings may destroy the transplanted myelin-producing neuroglial ascendant cells and inhibit their maturation. Immunological disorder and anti-inflammatory treatments may thus be necessary. Another downside is that the demyelinated MS lesions are distributed across multiple locations throughout the system. An efficient medical aid would force the deep-rooted myelin-producing neuroglial ascendant cells to migrate to those sites. Interestingly, during general administration in mice, NS cells migrate to inflammatory demyelinating lesions and some become myelin-producing neuroglial ascendant cells and remyelinated axons. Most cells remained dedifferentiated and suppressed pro-inflammatory mechanisms.

Spinal injuries

Spinal injuries interrupt ascending and drizzling nerve fiber pathways and cause a loss of neurons and interstitial tissue, inflammation, and degenerative disorder.[35] The lesions cause a loss of movement, sensation, and involuntary management below the location of injury. There is no cure, and the commonest current treatment of high-dose methylprednisolone is of questionable worth. The transplantation of stem cells into injured spinal cord can lead to functional benefits, mainly through trophic factor secretion or the remyelination of spared axons.[36] A recent study showed that human NS cells deep rooted into broken mouse funiculus generated new neurons and oligodendrocytes, resulting in movement recovery.[37] However, unless transplantation is monitored, there is a risk of development of undesirable effects. Astrocytic differentiation and aberrant axonal sprouting after NS-cell implantation into injured rat spinal cord can cause hypersensitivity to stimuli that are not normally painful.[38] Perhaps the most realistic short-term clinical goal is to use stem cells for remyelination, which probably occurs to some degree after lesions from endogenous oligodendrocyte precursor cells. One study rumored that during NS cell implantation into compromised funiculus in rats, there was a correlation between the amount of graft-derived oligodendrocytes, the quantity of fat, and therefore the extent of desired recovery. Another study published that transplanted oligodendrocytes from human ES cells may myelinate the injured rodent spinal cord and improve motor function.


  Conclusion Top


It might be premature to use stem cells to treat neurologic disorders. However, steady progress supports the hope that stem cell-based therapy helps to revive the function of brain and funiculus. For every disease, it is currently crucial to develop a road map that defines the scientific and clinical advances required for stem cells to succeed in the clinic. Before initiation of stem cell therapies to patients, one must be able to control the proliferation and differentiation of stem cells into specific cellular phenotypes and to prevent tumor formation. Moreover, the efficaciousness of stem cells and their mechanisms of action should be demonstrated in animal models, with pathology and symptomatology resembling the disorders in humans. Even so, it may be difficult to correlate data obtained in animals to humans because of species differences in the degree of neuronal plasticity and an incomplete knowledge of disease mechanisms. One must understand how to influence the pathological tissue environment, including inflammatory and immune reactions, to allow efficient repair. Exciting the neurobiological mechanisms might be the clinical usefulness of stem cells; however, it must be remembered that significance of stem cell therapy will be determined by their ability to provide safe, long-lasting, and substantial improvements in the quality of life of patients with neurological disorders.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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