Embryonic Stem Cells Potential Applications In Neurotoxicity Testing Biology Essay

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Embryonic stem cell are a type of pluripotent cells that are derived from the inner mass of blastocyst which is a state of embryo after 4-5 days of fertilization, these cells have an ability to grow indefinitely in their undifferentiated state, also these can be differentiated into all cells in the body. These are different from stem cells in a way that these are collected from embryo and also these are very dynamic cells that can differentiate into any type of cells in the body. This property of these cells can create a new revolution in the field of medicine because these cells can cure the most incurable diseases like genetic diseases and various types of cancers without the problem of rejection by the recipient body and also without tissue shortage (Anne E. Bishop.et.al)

As these cells are extracted from blastocyst , there is variety of ethical issue involved in the extraction of human embryonic stem cells because when a couple comes for an in-vitro fertilization, the embryos are formed in excess such that there is a better chance of pregnancy after implantation, the cells that are in excess are stored in freezing temperatures and if the couple agrees for the terms of use of their embryos than only can the researcher use these cells for embryonic stem cell research.

Teisha Rowland, Human Embryonic Stem Cells: A Decade of Discovery, Controversy, and Potential, published by all things stem cell on Apr 19th, 2009

Importance in Research and Therapy:

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Due to the versatile nature of these cells, it is seen that in these cells have a true capacity to differentiate themselves into various kinds of cells like blood cells, neural cells, muscle cells, pancreatic cells etc which intern can lead to cure of diseases like Alzheimer's, leukemia's, arthritis, and also diabetes. There are several researches going on individually for each diseases using human and mouse embryonic stem cells, so far this research has not been able to prove itself in the clinical trials but scientists are hoping to achieve more out of these cells as the advancement of more precise and accurate technologies come into existence.

Submitted by Mohit Joshi on Mon, 10/18/2010 - 08:55 on TopNews.in

As shown in the Diagram this is the true potential of stem cells especially human embryonic stem cells. The colonies of these cells can be useful in development of various different body tissues like Bone, adipose, cardiac muscle, gene delivery, neuronal cells and many more. Even in the near future these cells can be helpful in producing fully grown organs like heart, liver, pancreas etc. Overall studies have indicated that these cells can produce over 200 types of different varieties of cells that are found in an adult human body.

NUEROTOXICITY TESTING:

Neurotoxicity occurs in the presence of a natural or an artificial agent which are called neurotoxins. These agents are responsible for either disruption or killing of neurons that are present in the brain of an individual. Neurotoxicity can occur by radiations, chemotherapies, drug therapies also from heavy metals, food and pesticides. Symptoms of neurotoxicity is shown very early like blurry vision, numbness of limbs, loss of memory, delusions, headache etc.

Degree of neurotoxicity depends on time and degree of exposure of the respective agent.

It can prove fatal if not treated immediately, common treatments include use on chelating agents basically depends on the type of neurotoxin that is exposed.

As stated by Anna K. Bal-Price.et.al, Environmental changes effects more in children then in adults, as the developing brain is much more vulnerable to injury than the adult brain. This is because BBB (blood brain barrier) of a developing brain is not adequate enough to prevent the entry of chemicals even in the pregnancy placental layer is no strong enough to stop certain chemicals to pass through them into the embryo and if not checked these chemicals can cause variety of abnormalities in the growing infant like abnormal growth, mental imbalance and even death, these effects can vary according to the time of exposure and absorption rates. (Anna K. Bal-price.et.al). So it is really crucial for us to get as much data as possible regarding the toxicity of as much chemicals as we can. Recently there has been a great awareness and concern in this field due to the lacking of data of many chemicals that can be potential neurotoxins (P. Grandjean.et.al,). One proposed solution for these problems are to introduce High throughput screening (HTS) of chemicals which will enable us to know about the neurotoxicity of metals at a very high speed. So it is important that there should be use of different types of embryonic stem cells and compare these cells on the grounds of nervous system development properties like migration, differentiation and synaptogenesis. (S. Coecke.et.al).

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Basically there are two types of embryonic stem cells that are found nowadays, these are from mouse origin that are called Rodent models and Human Embryonic stem cells that are called human models each of them have their own advantages and disadvantages, and both of them are used in their respective fields very frequently and widely, lets discuss their pros and cons

Rodent Models: As described by Joseph M. Breier.et.al, Rodent embryonic stem cells or ESC's are basically derived from mice/rats and their embryos.The main advantage of using animal embryonic stem cells is that use of these avoid ethical concerns and also it is much easier to extract cells from animal's foetal tissue than from human because these cells are available in larger quantities and are also easily approachable.

Many rodent models are now available in the market now days. "These include ES-D3 embryonic stem cells. These were first isolated from the blastocyst of the 129/Sv mouse" (T.C. Doetschman.et.al). "These cells were used in the formation of dopaminergic neurons (J.H. Kim.et.al) has been used by De Groot and co-workers to differentiate ES-D3 stem cells into the cell types present in the CNS. In 23 days of culturing, the ESC's appearing to differentiate into mature and immature neurons, astrocytes and oligodendocrocytes since cells express markers of mature neural cells".

The main disadvantage of using these cells is that these are derived from animal origin; these don't give significant results when introduced into the human body. Also they behave differently when introduced in the body, these cells are basically used to get data and for literature regarding stem cell research but are not that widely used when it comes to diagnosis and therapy. One more concern with these cells is that isolation and maintenance of these cells are labor intensive and also expensive for many researchers.

Human Models: due to above mentioned causes it is very reasonable to use human embryonic stem cells because apart from ethical issues these cell lines have greater tendencies to mature and differentiate into the required cell lines. There are currently 21 available cell lines that are approved by NIH( National Institute Of Health) several of which can be differentiated into neuronal cells (NIH Human Embryonic Stem cell Registry, 2008).The reason that these are more practical nowadays is because these cell lines are commercially available, what it does is that it makes the company responsible for the maturation and development of these respected cell lines however it does not make researcher completely free of his responsibilities but it somehow saves time and efficiency of the researcher in maintenance and isolation also these cell lines give better results when induced in the body than the animal models. Some of the examples of these cells are Embryonic neural (EN)Stem-A cells(Millipore,Inc.) are a hNPC(neural progenitors cells) line derived from the NIH-approved H9 human embryonic stem cell line(J.A. Thompson.et.al), which has a normal female (46XX) karyotype and also ENStem-A cells express the SOX2 (Breier and Shafer, unpublished). According to the supplier, ENStem-A cells also differentiate into multiple neuronal subtypes, including cholinergic, dopaminergic, and GABAergic neurons, glia, and oligodendrocytes, and maintain a stable karyotype for at least ten passages, These are the cells that have the potential to be the main cells for the HTS approaches as direct effects of chemicals on these cells can be assessed.

Potential application in neurotoxicity testing:

Rodent Models: Several studies have been conducted so far in the Murine NSC's(Neuronal stem cells) including the effects of endocrine disruptors(K.S. Kang.et.al), lead(F.N. Huang.et.al), methyl mercury(N. Onishchenko.et.al) and studies of Chris toffer et.al showed that NSC's are more sensitive to different toxins than differentiated neurons, neuronal or glial cell lines and they have proven that these NSC's are the more valuable models for neurotoxicity testing. Moreover, De Groot and colleagues (J. Lammers.et.al) have been developing high through put studies using different procedures and techniques that involve use of these ES-D3 cell lines. In one test they have check the effect of neurotoxins on these cells by staining with general Haematoxilin and Eosin(H&E) stain and are classified on the basis of their morphological features. These cell cultures are then developed and quantified using stereological principles (H .G. Gundersen, .et.al) (FIG-3). The main advantage of using these cell lines in this test is that these cells are more sensitive and responsive to neurotoxins than the mature differentiated cells.

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After the staining with Haematoxilin and Eosin(H&E) stains these cells are counted and quantified using standard operating procedures and then the results are plotted in the form of graph which clearly shows the effect of neurotoxins in different varieties of cells and also the amount of cell died can predict the mortality rate of a particular toxin, that is why it is crucial to test these toxins as quickly as possible but it is not the case in these cell line because this assay takes a long time to complete because these cells take long time to differentiate in cells that can give significant results although use of 96 well plates is more suitable for high throughput studies(A. Fico.et.al). But the time factor cannot be ignored in the case of rodent models

FIG-3 shows cell stained with Haematoxilin and Eosin(H&E) stains in part 1 there are different types of cells denoted by C1,C2,C3,C4,C5,C6,C7,C8,C10. The stained cells in part I is showing the effect of neurotoxin in different types of cell whereas part II shows the graph of percentage of viable cells to types of cells, the fig clearly shows that only C2 are the cells with highest viability as these cells are NSC's these are more resistant to toxin and C9 are not shown because these are dead cells due to the effect of this toxin. (Breier J.M..et.al,. Nuerotoxicology and teratology 32 (2010) 4-15, pg-9)

Human Models: Number of studies has used Human neural progenitors cells which are derived from Human embryonic stem cells, these cells have been used as good subjects for neurotoxicants but only a few numbers of chemicals have been tested so far. So much work has to be done in this field. Generally the basic research using these models has been done so far using only one approach or using only one type of chemicals at one point so there is a considerable amount of research that is yet to be done using these models with high throughput studies and different varieties of chemicals at one point of time, let us see one research of chemical effects on ReNcell CX proliferation and viability in a high-throughput/high-content format(J.M. Breier.et.al).This study is also included in main research which uses high throughput study and other different assays that will allow us to know more about neurotoxin capabilities of these chemicals . This study showed that there were about seven chemicals that had neurotoxic ability which was not previously mentioned. ReNcell CX cells have also been used recently to examine the effects of 320 pesticides (primarily) compounds on proliferation and viability (K.A. Houck.et.al). While full analysis of the data is pending, this demonstrates the ability of this approach to screen large numbers of chemicals. Thus, with more intensive work on these cells in the future can make this cell line a very valuable model for research in this field however it is apparent that more work is required before reaching to this conclusion.

CONCLUSION:

The use of embryonic stem cells is still a very emerging field; most of the work in this field is done in 3-5 years. There are still different varieties of areas that are needed to be assessed and determined. The problems regarding the effect of different chemicals on neurons should be addressed on a larger scale and these studies should be periodically updated and should be notified to common people too, only that's how there will be awareness among general public about the use of these general chemicals. There is also some aspects of this research that are still not clearly understood by the researchers like they know stem cells differentiate into different types of cell but how does this happen is still not clear. So as we progress technologically there will be emergence of new techniques that will enable HTS studies into a new level. Researchers are trying to improve these studies to be more efficient and fast. It is clear from these studies that In the near future the clues that are not known now will be clear and the technologies will be precise and accurate. For e.g., Collins et al, Recently proposed introducing alternative methods for toxicity testing. They proposed that instead of using high throughput studies which allows the evaluation of approx 10,000 chemicals per day, using of medium throughput studies in different animals at one time will allow us to test 100-10,000 chemicals/year but in this case we will have the effect of these chemicals on different species of animals and also it will help us to evaluate the different mechanisms by which these embryonic stem cells work more efficiently and with more accuracy. In the near future we can see some significant results from this area of study because there is a lot of information that is still not available in literature about these stem cells so as more and more pieces of this puzzle will come into play we can expect some remarkable and world changing cure or medicine that can treat even the most deadliest of diseases with greatest of ease.

So in conclusions I will say that this field of study is full infinite possibilities and studies also will definitely improve the neurotoxicity testing in the future.