By Janice Siu Yan Hui


Huntington's disease (HD) is a neurodegenerative genetic disorder caused by a mutation in the gene Huntingtin, leading to selective death of GABAergic projection neurons in the striatum, constituting vital parts of basal ganglia loop circuitry. As a result, symptoms of HD include poor coordinating movement, cognitive decline and dementia. Many have tried to find different methods in curing, if not, improving the symptoms of Huntington’s, and studies have shown that there is actually repair in functionality of the damaged circuit of GABAergic neurons with the use of neural stem cells after intracerebral transplantation [1] . Furthermore, neural stem cells were also proven to be useful in rat models induced by striatal quinolinic acid (QA) injection (showing ongoing striatal degeneration, much like HD)[2] . These neural stem cells have been observed to migrate into the striatal lesion and decrease degeneration of cells, as well as inducing long term functional improvement in symptoms[2].

Use of different stem cells for Huntington’s disease therapy

Throughout many years of research, scientists have used a variety of stem cells in attempt to relief and stabilize the symptoms of Huntington’s disease, including the use of adipose stem cells[3] ,[4] ,[5] , bone marrow mesenchymal stem cells[6] ,[7] , neural stem cells[2],[8] ,[9] , and induced pluripotent stem cells[16], where each of these stem cells have different regenerative mechanisms towards HD.

Adipose stem cell

Adipose tissues are the main origin where adipose stem cells (ASCs) are obtained from, as well as being one of origins of mesenchymal stem cells. It has been discovered that ASCs have differentiation capacity, and their ability to structuralize themselves like neurons and Schwann cells results them to be identified as pluripotent stem cells[3]. ASCs have been used widely for many researches as regenerative medicine for human therapy in neuroscience due to its expendability and availability[3]. As a result, ASCs were used to experiment its beneficial effects on Huntington’s:

With the use of a murine model induced with quinolinic acid (QA) (resulting mice to have symptoms of HD), it was established that human ASCs had the ability to slow the progression of HD when they were transplanted into them[4]. The murine model expressed neuroprotective genes and reduced symptoms of rotational behaviour, with a decrease in lesion volume and apoptosis in the striatum (due to a decrease in the level of N-terminal fragments of mutant huntingtin)[4]. It was also found that there was an increased expression of PGC-1α, which is a transcriptional coactivator (regulating the genes involved in energy metabolism)[4].

In another study, scientists have analyzed the difference between HD ASCs and normal human ASCs; although similar in terms of multiple growth factors expression, HD ASCs lacked nerve growth factor[5]. Furthermore, they have compared the outcome effects of HD ASCs and normal ASCs transplantation in a yeast artificial chromosome (YAC) mouse model of HD (YAC128)[5]. It was observed that when both versions of ASCs were transplanted into 8 month-old YAC128 mice, there was a decrease in striatal atrophy with normal ASCs at the age of 12 months, but none of this was observed with HD ASCs transplantation[5]. It was also discovered that the effectiveness of ASCs transplantation is dependent on when they were transplanted into the transgenic murine models[5]; in other words, ASCs efficacy can be modified. This point was noticed where there were no signs of improvement in the Rotarod performance in both YAC128 control group and transplanted YAC128 mice; but when normal ASCs were transplanted in 12 month-old mice instead of 8-month old, there was a conservation of Rotarod performance for 4 weeks[5].

Bone marrow mesenchymal stem cell

Mesenchymal stem cells (MSCs), also known as bone marrow stromal cells, have become a potential component in cell therapy for neurodegenerative diseases. MSCs can be transplanted into the brain via intrathecal (the space under arachnoid membrane of the brain/spinal cord) or intracerebal injection, which promotes endogenous neuronal growth, recovery of damaged synaptic connection, and decreases apoptosis and free radical levels[6]. The powerful mechanism behind MSC is its ability to produce growth trophic factors, such as brain-derived and glial-derived neurotrophic factors, which induces regeneration and survivability of damaged neurons in the brain[6].

To further elaborate that point, Wislet-Gendebien et al.[7] revealed that cytokines and chemokines were secreted from implantation of MSCs in order to promote a better environment for neuroprotection and regeneration of injured neurons, as well as increasing neurogenesis and decreasing atrophy in the striatum. In a rat model of HD, MSC was transplanted into the damaged striatum and had evidenced that although the cells have remained undifferentiated, they produced trophic effects and reduced working memory deficits[6]. Findings also showed lateral ventricle volumes returning to a smaller size and striatal atrophies being significantly reduced, which manifests MSCs’ potentiality to treat defects in motor disorders of HD[6].

Additionally, MSCs have the capacity to migrate robustly (in response to a brain injury); even when they were implanted at adjacent sites of the damaged areas, they were able to help delay the loss of medium spiny neurons from HD and help augment the recovery and survival of striatal neurons[6]. Due to its ability to migrate distances, MSCs have regenerative influence on the damaged striatal dopaminergic nerve terminal network in a QA animal model of HD[6].

Neural stem cell

Gaura_et_al_-_before_and_after_graft_image.jpgNeural stem cells (NSCs) are effective in terms of motor and cognitive improvements, as well as brain metabolic activity recovery in damaged striatal regions[8]. Bachaud-Levi et al.[8] did a long term study on five patients with Huntington’s with NSC intracerebral transplantation and recorded its effects on HD for six years. Results showed that three out of five patients benefitted from NSC transplantation, including clinical improvements on striatal and cortical hypometabolism, verbal fluency, motor performances, executive function tests[9], and stability of cognitive performances, but only for the first two years as they began to plateau and declined variably four to six years after surgery; the last two patients continued to deteriorate with HD[8] with progression of striatal and cortical hypometabolism (which can be seen in Figure 1)[9]. In other words, intracerebral transplantation of NSC in HD patients has the ability to reconstruct the damaged cortico-striatal loops.

Furthermore, NSCs have the capacity to migrate to impaired sites in the brain to promote neuroprotective effect in QA mice model[2]. It was seen that NSCs can travel to striatal lesion, decreasing striatal atrophy and inducing long term functional improvement in symptoms[2].

Current animal models of HD

As mentioned above, there were quite a few studies on rodent models with QA injection demonstrating HD. In a QA model, glutamate receptors are stimulated, which resembles the features of HD patients[10] . Various different types of stem cells, such as the few listed above (ASC, MSC, and NSC), were used on these models and produced varying results regarding clinical improvements of the disease. Currently, the most successful HD models are QA and ibotenic acid models; kainic acid models lost out in experimentation due to the fact that kainic acid injections induced other clinical declinations which do not usually occur in HD patients, including epileptic activity and neurodegeneration in the hippocampus and limbic structures[11] .

Rodent models with quinolinic acid, kainic acid, and ibotenic acid injection

One thing to point out is that there are differences and similarities (in terms of neurotoxic properties) between all of the excitotoxin injections. It was noted that quinolinic acid shares a number of characteristics with kainic acid, such as preferential degeneration of pyramidal cells in the hippocampus, cortical deafferentation leading to prevention of striatal neurotoxicity, and reduced excitotoxin in the striatum[11]. Despite these similarities between the two kinds of injections into an animal model, QA was thought to be better than kainic acid injection due to the number of problems kainic acid injection caused. As a result, ibotenic acid injection also became more recognized than kainic acid as ibotenate can create an ideal depiction of what is exactly happening in a HD patient/excitotoxic rat model[11].

One of the most mentioned rodent model is the QA model by Lee et al.[2], demonstrating functional recovery from NSCs transplantation. This type of transplantation allowed neurotrophic factors production which helped to protect the striatal neurons from the excitotoxins[10]. Furthermore, through various scans and analysis, it had been thought that stem cell transplantation could be effective if it was surgically done earlier before the onset of HD[10].

In addition to the more common rodent models of HD, there is another chemical called 3-nitropropionic acid (3-NP) which leads to similar behavioural deficits associated with Huntington’s, caused by neurodegeneration in the basil ganglia (which led to motor function dysfunction) and impairment in the organisms’ metabolism[10]. Administration of 3-NP was found to interfere with ATP synthesis, but when human NSCs were transplanted into the striatum of 3-NP rat models of HD, there were significant improvements in motor functioning and development in better resistance to damage in striatal neurons, which might be due to brain-derived neurotrophic factors (BDNF) secreted from the NSCs[10]. Again, experiments were held to contrast the effects of human NSCs implantation at different time window in 3-NP rodent model, and it showed that rats with intrastriatal implantation a week before 3-NP administration displayed improved and better motor performance and reduced striatal neurons damage compared to control groups with saline injections; however NSCs implantation twelve hours after 3-NP administration did not show any improvements at all[12] . In other words, it can be confirmed that the idea of transplanting NSCs to predetermined HD patients can significantly improve clinical symptoms compared to transplanting NSCs after being diagnosed with HD.

Transgenic rodent models

Transgenic rodent models are different from normal rodent models of HD as transgenic models require genetic engineering to transfer the genetic material that produces symptoms of HD, whereas rodent models are used in a way to match the physiology of the symptoms and see how they react to treatments.

Although the main aspect of these models is to experiment different treatments of HD and observe their effects, other transgenic mice models out in the field of neuroscience have been used to conduct research on the different effects of HD according to different traits of the organism, including sex differences[13] and age differences[14] . When each gender was examined for differences from the other gender, Bode et al.[13] discovered that males of a transgenic HD model exhibited motor function impairment and a loss of DARPP-32+ medium-sized spiny neurons due to a decrease in dopamine D1 receptors and levels of 17β-estradiol. Because of this, it can be assumed that sex hormones play an important role in neurodegenerative diseases like HD, which can be applied to new perspective of HD therapy. Additionally, R6/2 transgenic mouse model of HD displayed varying vulnerability of the striatum towards glutamate excitotoxicity at different ages: at 10 weeks, both R6/2 transgenic HD mice and wild-type mice were vulnerable to glutamate toxicity, but only R6/2 mice presented more destruction on the striatum at 14 weeks[14].

More recently, Walker et al.[15] focused on hippocampal precursors and neural precursors in the subventricular zone in R6/1 transgenic mouse model of HD. The results were interesting in a way that light can be shed on more advanced and better ideas in trying to relief and/or cure the symptoms of HD. In this transgenic mouse model, subventricular zone precursors declined as the mouse aged in both wild-type and HD mouse; however there were small latent hippocampal precursors and stem cells maintained in vivo even though there was a declination of hippocampal precursors in wild-type mice[15]. In other words, there is potential that the preservation of stem cells and hippocampal precursor can be activated to improve HD symptoms despite a loss of neurogenesis.

Contribution of induced pluripotent stem cells in human HD cell model

The idea of generating induced pluripotent stem cells (iPSCs) strives to bring us one step closer to human trialing. iPSCs, extracted from an adult somatic cell, are made to express certain genes (in this case, the expression of HD genes) and have the potential to differentiate into any of the germ layers. Zhang et al.[16] cultured normal iPSCs and HD iPSCs and discovered that both have the ability to form embryoid body immediates, which give them the potential to develop into appropriate cell types of HD. Furthermore, human HD NSCs were also cultivated and they have noticed that these NSCs can differentiate into striatal neurons, as well as GABAergic neurons and DARPP-32+ neurons[16]. At the same time, HD NSCs were found to have an increase of caspase activity (important in cells during apoptosis) compared to normal NSCs, which can be served as a new insight in developing other therapeutic methods in treating HD patients and creating better animal models of HD[16].

Transforming Growth Factor-Beta (TGF-Beta) signalling in the brain

TGF-beta molecules are used in many different kinds of cell activities, including differentiation, proliferation, regeneration, and the formation of the extracellular matrix[17] .

TGF-Beta1 levels

TGF-beta1 will mainly be discussed here as it is a major regulator of adult neurogenesis by decreasing the amount of proliferating cells[17], potentially driving another path forward to cure HD. In a neurodegenerative disease like HD, TGF-beta1 levels and its downstream signalling factors were reported to have increased even though neurogenesis is already impaired in the brain[17]. However, on the bright side, NSCs are seemed to be induced due to the inactivation of TGF-beta1 signalling, which helps the preservation of stem cells in HD patients, allowing their brains to regenerate numbers of neuronal loss[17]. As a result, migration of the inactivated TGF-beta1 from the subventricular zone to the striatum[17] can greatly facilitate the regeneration of neuronal and functional loss in HD patients.

External Links

1) Huntington Society of Canada
2) Stem Cell Research in Huntington's Disease


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