Stem cell therapy for neurodegenerative diseases:
Progress and prospects
© 2004 Mykola Kovalenko, Dnepropetrovsk, Ukraine, May 2004
Although neurodegenerative diseases have different causes, the dysfunction and loss of specific
groups of neurons is common to all these disorders and may allow the development of similar therapeutic
approaches to the treatment of diseases like Alzheimer’s disease (AD) and Parkinson’s disease (PD). The
efforts to treat the neurodegenerative diseases by existing methods of cellular therapy are insufficiently
effective. The modern methods do not provide correct restoration of cytoarchitecture and pattern of
connections (the rewiring of specifically organized long-distance connections), which are essential to
achieve a significant functional recovery. This article discusses existing methods of neural stem cell
therapy and provides example of new approach to the treatment of various neurodegenerative diseases.
Neurodegenerative diseases are an assortment of central nervous system disorders characterized by
neuronal loss and intraneuronal accumulation of fibrillary materials. Abnormal protein-protein
interactions may allow the precipitation of these proteins, forming extracellular and intracellular
aggregates. These abnormal interactions could play a role in the dysfunction and neuronal death that
characterizes several common neurodegenerative diseases, such as Alzheimer’s Disease (AD) and
Parkinson’s Disease (PD).
AD is the most common cause of dementia, with aging a major contributor to its onset. Currently,
it is estimated that 40% of people over age 80 are afflicted with AD. Autopsy examination of a patient’s
brain reveals gross cerebral atrophy, signifying loss of neurons and the presence of large numbers of
extracellular neuritic plaques and intracellular neurofibrillary tangles. Plaques and tangles are found
predominantly in the frontal and temporal lobes, including the hippocampus. In more advance cases, the
pathology extends to other regions of the cortex. Similar plaques and tangles do occur in normal ageing
brains.
PD is more common in people 60 years old and older. In the US, PD affects 1.5 million people.
The degeneration and loss of dopaminergic neurons in PD causes akinesia, rigidity and tremor. Cell
transplantation for the treatment of PD is the promising approach that has received most attention.
Cell therapy for PD
The potential of cell therapy for neurodegenerative diseases was demonstrated on implantation of
different types of stem cells in the animals with PD (Kim J-H et al 2002, Parati EA et al 2003).
Transplantation of stem cells into rat brain resulted in reinnervation of the striatal neurons and partial
recovery of motor deficit associated with dopamine deficiency (Kim J-H et al 2002). The same results
were obtained after transplantation of fetal dopaminergic neurons in clinical trials (Piccini P et al 2000,
Freed CR et al 2001). It is possible to use different types of stem cells to generate dopaminergic neurons.
Today the process of dopaminergic neurons differentiation from embryonic stem cells (ESC) in vitro is
most effective and understandable (Kim J-H et al 2002, Isacson O, Ann Neurol 2003, Isacson O, Lancet
Neurol 2003, Barberi T et al 2003). Recent progress in human therapeutic cloning (Woo Suk Hwang et al
2004) makes this way to generate neurons more and more attractive. Differentiation of ESC in vitro and
transplantation of dopaminergic neurons in the animal models of PD resulted in functional integration of
implanted cells into recipient’s brain and partial recovery of motor functions (Kim J-H et al 2002, Barberi
T et al 2003).
Although transplantation of neurons into striatum in PD model has a higher effectiveness in
comparison with transplantation of neurons in other neurodegenerative disorders, it is too early to speak
about full restoration of motor deficit associated with parkinsonism. In case of PD significant functional
recovery requires cell replacement with, at least partial repair of original connections with neurons in the
striatum. If such connections do not exist the full regress of motor deficit is impossible because dopamine
release is under feedback control. This fact emphasizes the importance to develop effective methods to
stimulate axon growth in correct directions.
Figure 1 A). Zone of progressive degeneration of neurons. B). A typical result of stem cell
transplantation. Unregulated migration and undirected growth of neurons, random synaptic connections.
Result – low effectiveness of therapy. C). Wishful result of transplantation. To gain maximum effect the
transplanted cells have to differentiate in the neurons, duplicate geometry and reestablish synaptic
connections of dysfunctional (or apoptotic) cells with maximum accuracy.
The method to enhance accuracy of regeneration (Potential therapeutic strategy)
After transplantation stem cells make decisions regarding fate and patterning in response to
external signals from extracellular environment and neighboring cells. The effectiveness of neural stem
cell therapy may be facilitated by the ability to manipulate these signals in a temporal and spatially
appropriate fashion (Liu CY et al 2003). The future methods of therapy could include in vitro processing
of stem cells before implantation, supporting and guiding the cells after implantation with the help of
nanorobots, as well as the in vivo creation of molecular scaffold (The Samuel I. Stupp Laboratory sistagirl.ms.northwestern.edu, Silva GA et al 2004) for stimulating their growth in the correct direction.
During experiments on neonatal rats (Englund U et al 2002) the potential ability of neural stem cells to
establish appropriate long-distance axonal projection after region-specific differentiation were shown.
Unfortunately, adult brain, as compared to neonatal, has unfavorable conditions for axon growth in the
correct direction. It is for this reason the stimulation of new neurons growth, for example along the surface
of neurons in the zone of progressive degeneration, is necessary (Figure 1C, Figure 2). The
reconstruction of dysfunctional neural circuits may be facilitated in the following way (Figure 2). The
proposed strategies are designed to increase accuracy of dysfunctional neurons regeneration.
Figure 2
A). Neural stem cells and nanorobots.
B). Stereotaxic implantation of stem cells and nanorobots in the zone of progressive degeneration of
neurons. Delivery of stem cells and molecular cues, which consist of (for example) neural growth factor
(NGF) or laminin, on the surface of dysfunctional neurons. Creation of molecular “niches” along the
surface of dysfunctional neurons.
C). Controlled growth of new neuron along the surface of dysfunctional neuron with the help of
nanorobots. The new healthy neuron inherits the properties of old neuron owing to environmental
conditions (Bjorklund LM et al 2002, Englund U. et al 2002).
D). Apoptosis of dysfunctional neuron.
This therapeutic strategy shall become possible after development of the technology for controlled growth
of neurons along the surface of target (dysfunctional) neurons. One of the most promising approaches lies
in using of nanomedical technologies (Freitas RA Jr., Nanomedicine) and nanorobots* in particular.
Functions of nanorobots (Figure 2):

Delivery of stem cells in the zone of progressive degeneration of neurons.

Recognition of dysfunctional and apoptotic neurons.

Creation of molecular niches for stimulation of new neuron growth along the surface of old
one.

Control of replication of geometry and synaptic connections of old neurons by stem cells (by
new neurons).

Recycling of apoptotic neurons.
Evidently, using dysfunctional neurons as a “niche for growth” is one of the ways for sufficiently
accurate and safe regeneration of neuronal circuits. With gradual replacement of the dysfunctional or
apoptotic neurons the new neurons shall be integrated into existing cellular structure and, thus, be
involved in a thought processes without mental degeneration.
*A nanorobot is a specialized nanomachine designed to perform a specific task or tasks repeatedly and with precision. They
have dimensions less than 20 micrometers.
Nanorobots are of special interest to researchers in the medical industry. They have potential applications in the assembly of
small-scale, sophisticated systems. Nanorobots might function at the cellular level to build molecular niches and control the
process of cellular regeneration. See also www.nanomedicine.com
References
1. Barberi T et al, Neural subtype specification of fertilization and nuclear transfer embryonic stem
cells and application in parkinsonian mice. Nature Biotech, 21, 1200, 2003
2. Bjorklund LM, et al., Embryonic stem cells develop into functional dopaminergic neurons after
transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 2002; 99: 2344–49.
3. Englund U et al. Grafted neural stem cells develop into functional pyramidal neurons and integrate
into host cortical circuitry Proc Natl Acad Sci, 2002, 99, 17089-94
4. Freed CR et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N
Engl J Med 2001; 344: 710–19.
5. Freitas RA Jr., Nanomedicine, Vols. I & IIA, Landes Bioscience, Georgetown TX, 1999 & 2003;
http://www.nanomedicine.com
6. Isacson O et al. Towards full restoration of synaptic and terminal function of the dopaminergic
system in Parkinson’s disease by stem cells, Ann Neurol 2003; 53 135-148
7. Isacson O., The production and use of cells as therapeutic agents in neurodegenerative diseases,
Lancet Neurol, 2003, vol 2, 417-424
8. Kim J-H et al, Dopamine neurons derived from embryonic stem cells function in an animal model
of Parkinson’s disease, Nature, 2002, 418: 50-56
9. Liu CY, Apuzzo ML, Tirrell DA. Neurosurgery. 2003, 52(5):1154-65; discussion 1165-7.
Engineering of the extracellular matrix: working toward neural stem cell programming and
neurorestoration--concept and progress report.
10. Parati EA et al. Neural stem cells. Biological features and therapeutic potential in Parkinson's
disease. J Neurosurg Sci 2003. Vol.47. №1. 8-17.
11. Piccini P et al. Delayed recovery of movement-related cortical function in Parkinson’s disease
after striatal dopaminergic grafts. Ann Neurol 2000; 48: 689–95.
12. Silva GA et al. Selective Differentiation of Neural Progenitor Cells by High-Epitope Density
Nanofibers, Science 2004, 303, 1352-55
13. Woo Suk Hwang et al, Evidence of a Pluripotent Human Embryonic Stem Cell Line Derived from
a Cloned Blastocyst, Science 12 March 2004; 303: 1669-1674