Stem+Cells,+Cell+determination,+and+Cell+Signaling

By: Anna Kasdan, Allessandra Farrar, and Sydney Goldman



__What is a Stem Cell?__
Most of our cells are known as ground cells. At their creation, they are differentiated to have one function, such as to act as skin, hair, or an intestine lining. When such cells reproduce through mitosis, all of their offspring prove genetically identical and grow up to fill the same function as their parents. The rest of our cells, stem cells, are undifferentiated, meaning that they when they renew themselves through cell division, they can form either an identical copy of themselves--a new stem cell--or another variety of specialized cell. (1) Primarily used for initial growth and later maintenance of organs, stem cells, though first postulated about in the the 1880s, and discovered in bone marrow in the 1960s (4), remain vastly vague in our view and hold potential as solutions to diseases that are currently thought to be untreatable (9).

Two types of stem cells exist: **human embryonic stem cells** (hESCs) and **somatic**, or adult stem cells.

__**Characteristics of Embryonic and Somatic Stem Cells:**__ Human embryonic stem cells are collected, as the name implies, from a human embryo left-over from an in vitro fertilization procedure. Scientists remove their outer-most **trophectoderm** layer to access the cells in the interior of the blastocyst. Once collected, they are synthetically grown in a culture medium. Recipe-like cocktails of varying chemical composition are used in a process called directed **differentiation** to render **embryoid bodies** leading to specific types of specialized cells--conveniently enough, only the exact kinds the researchers seek are produced. If left in a plain culture medium, the embryonic stem cells would still create a crop of differentiated cells, but they would be of mixed variety. If a scientist were looking to isolate only one type of cell in a plain culture medium, she or he would need to hope that this unchecked process of "**spontaneous differation**" happens to make the desired kind of cells--making spontaneous differation incredibly inefficent. The ability to **directly differentiate** will hopefully lead to the direct transplant of masses grown from a host's modified, previously defective cells back into its body (8). This way, the immune system should recognize and not attack the introduced cells, allowing for a successful repair.

====In their natural environment, embryonic stem cells go through direct differentiation, eventually assembling all of the different types of cells that make up the human body. The ones that remain undifferentiated become **somatic stem cells**. They are responsible for the initial creation and continual maintainance of our organs and tissues. Located in small pockets of many structures such as the brain, heart, liver, teeth, and bone marrow, somatic stem cells are grouped together and surrounded by **niche cells** that help to regulate their function (10). Niche cells signal stem cells to stay undifferentiated. Without signals from a niche cell, a stem cell would turn differeniated, and if a niche cell dies, so does its stem cell counterpart. Though adult stem cells typically renew themeselves regularly, they can remain quiescent or non-dividing for long periods of time if they aren't needed to repair tissues from injury, wear, or disease.====

Until five years ago, scientists believed that only embryonic stem cells had the capacity to reproduce indefinitely any variety of cell--that adult stem cells could rigidly only give rise to say, blood cells, if they were found in bone marrow, and to no other variety. The quality of **plasticity** or the ability to differeniate into further types of mature cells than the cell naturally does is has recently been found in adult stem cells. During their differentiation process, the cell's DNA is tagged with **epigenetic markers,** indicating which genes are activated (9). Though which genes happen to be tagged by epigenetic markers can passed on to offspring, they can be activated, deactivated or added to DNA to change which genes are expressed--and in stem cells's case, changed the seeming fate of somatic stem cells. Depending on how tightly or loosely DNA is wrapped around histone proteins, different segments of DNA are exposed to the outside and available to be marked (11). In a stem cell, DNA is coiled around histones, but the coils are not further coiled on top of each other as in a differentiated cell. By uncoiling the supercoils of DNA and Histones of a differentiated cell, it becomes structed as the DNA and histone coils of an undifferentiated stem cell (9).



__Stages of Stem Cell Development__
As stem cells differentiate, they go through three stages. At first, stem cells are **totipotent**, meaning that once they have gone through fertilization they have the potential to develop into any type of human cell or organ. In some cases, they can even develop into an entire organism. After four days, stem cells become **pluripotent**. They now only have the ability to develop into tissues. At this point, the stem cell divides into two layers: the placenta and differentiated organ cells. Lastly, stem cells become **multipotent**. These cells lead to the formation of specific cells within a tissue or an organ.

__Neural Stem Cells (1) __
====Most abundant after the closure of the neural tube, neural stem cells have the primary effect on the central nervous system as their ability to generate new neural connections, increasing the amount of synapses in the brain through axon growth. The specific region of the axon that responds to molecular and chemical signals is known as the **growth cone**. As in most signaling processes, signal molecules from target cells bind to the growth cone, initiating a signal transduction pathway. **Cell adhesion molecules** (CAMs), which are attached to the growth cone, track the axon’s growth and response to signals. These molecules enable the axon, if damaged, to find the correct repair mechanisms, whether it be a protein or growth hormone. One important fact to note is that axons express different genes at different times, much as embryonic stem cells can develop into either brain, blood, heart, or skin cells if cultured correctly. **Neural progenitor cells** are the clones of the brain cells developed at birth, and will become nerve cells if brain cells are diseased or damaged, as brain cells cannot divide once they are fully developed. These progenitor cells (which comes from the Latin verb progenitor, meaning "to be born") can differentiate into cells that may become either neurons or glial cells. Glial cells are the neuron's support system, surprisingly outnumbering neurons fifty-fold. **Astrocytes** provide structure and metabolic regulation for the neurons, and **oligodendrocytes** form myelin sheaths around the axons in the CNS. Both the astrocytes and oligodendrocytes aid the neurons in terms of structure and fucture; there is much interaction between the neurons and the glial cells that develop from neural stem cells.====

__Current Research on Stem Cells__
====Recently, researchers have experimented with neural stem cells and Alzheimer’s. There are two main factors that contribute to the loss of cognitive abilities in Alzheimer's: accumulation of plaque and the loss of neural connections. Researchers implanted stem cells into both halves of the hippocampuses of mice and found that they increased the amount of synapses formed, but had no effect on the increased levels of plaque accumulation. (2)==== ====FGF (**fibroblast growth factor**) slows differentiation “and can hold stem cells in stasis under laboratory conditions if needed”. It has been found through studies performed on rat embryos that FGF has a profound effect on neural stem cells. FGF2, a subset of FGF, leads to increased cortex size and levels of excitatory neurons. Recent research suggests that antidepressants may work with FGF2, thus increasing brain activity. (2) ==== ====Stem cells have been found in umbilical cord liquid (blood). Unlike embryonic stem cells, these are much easier to handle and cultivate in a laboratory setting, and they do not mutate into tumors, as can be the case with embryonic stem cells, as they follow similar signaling and pathways to those of cancer cells. Pro-life folks possess more support for amniotic stem cells research than embryonic stem cell research because the “life” of an embryo is not destroyed. In one experiment done at the University of Minnesota, stem cells were transplanted into the brains of rats who had been induced with strokes. The cells “took on” the qualities of neurons, despite the previously held belief that these stem cells could only differentiate into blood cells. (4) (5) ====

Hopefully, stem cells will be able to cure many other degenerative diseases, such as Parkinson's.
Some scientists speculate that cancerous masses may just be out of control stem cells, so as more is discovered about both the behaviour of stem cells, perhaps new treatments for cancer could be simultaniously developed (8).

Many transplants performed today are done without the use of stem cells. The success rate for these transplantaions is low, as the body may recognize the structure or substance (such as blood in a blood transplant) as foreign, thereby creating anitbodies to fight what it deems to be a "foreign anitgen" (the genetic markers on a foreign object are different and the receptors would not match the receptors of the patient). Recently, a quadruple-limb transplant was attempted on a Turkish citizen. Unfortunately, the transplant was unsuccessful and the patient died shortly after. However, scientists are working to increase the number of transplants performed with stem cells.

Stem cells have use in transplants of defective or infected tissues. In one kind of transplants few adult stem cells are isolated from a patient (we have many fewer stem cells than ground cells, so we must be careful not to remove a harmful amount). The cells are labeled in a cell culture with molecular markers that influence their differentiation into specific types of cells (8). Once new healthy and effective cells grow, they are reinserted into the original tissue in hopes that they will successfully repopulate the area. The transplanted tissue is not rejected by the immune system, because it was rooted from a stem cell that it recognizes as "self". If adult cells from another person or other animal were used, they would likely be rejected by the patient's immune system, and immunorepressive drugs with intense side effects would need to be administered. That's why the other common type of transplant uses embryonic stem cells that are young enough in their development that they are perceived as neutral or **immunologically undefined** by the immune system and should be able to be accepted by any body (8).

Though these transplant procedures prove to be successful, scientists hope to develop ways to trigger stem cells to replicate while still inside of the body: a completely non-invasive procedure with no risk of immune rejection of foreign bodies, because a patient's own cells would be used.

Another recent and major field of stem cell research involves **induced** **pluripotent stem cells**, mature cells that are retrograded by manually activating and disactivating certain genes, reverting themselves to have the same genes turned on as a stem cell in the pluripotent stage of development would be active. Most work regarding induced pluripotent stem cells has involved **transgenic gene therapy** using mice (8). Certain traits, such as the capacity for sickle cell anemia are tested by creating embryonic stem cells with genes targeted to bring about these traits that are implanted into a female mouse's uterus. Her offspring would be tested and mated in various combinations to test how widespread the trait proves to be and project their findings on how the diseases would affect humans (13). 

__Signaling in C.elegans (1) __
====The nematode //C.elegans// provides a stellar example of cell signaling during embryonic development. Primitively, **induction**, when cells signal their neighbor cells to change in a specific way, often involving conformation, causes differentiation. //C. elegans// has an opening through which it can lay eggs, known as a **vulva**. A signal cell attached to an anchor cell determines the fate of the vulva cell; it secretes an inducer and this part becomes the inner vulva. Similarly, when another inducer (known as the **second inducer**) binds to the anchor cell surface, the outer vulva is formed if it correctly transduces the signal. Lastly, if the signaling fails, then the vulva cells known as the “**vulva precursor cells**” become part of the neighboring epidermis. Thus this embryonic differentiation in //C. elegans//, a simple organism because of its small genome, depicts how induction (first inducer) and cell surface signaling (second inducer) leads to the development of vulva and many other parts in nematodes, reptiles, and humans alike.====

[[image:http://news.bioscholar.com/wp-content/uploads/2010/07/C-elegans.jpg width="192" height="158" caption="C.elegans "]]
__**Signaling in Blood Stem Cells** (6) __

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Complex signaling exists between blood stem cells in the **placental niche**. The placental niche "plays a key role in stopping blood stem cells from differentiating into mature blood cells in the placenta. The placental niche allows blood stem cells to grow without becoming mature blood cells, thereby acting as a safe guard. These cells are known as precursor cells, as they are the "precursors" to mature blood cells that may develop later in fetal development. A specific signaling pathway, known as PDGF-B, was found in the trophoblasts, which regulate the exchange of nutrients between the mother and the fetus. Trophoblasts have been found to "act as powerful signaling centers that govern the niche safe zone." When PDGF-B signaling is disrupted or ceases, the precurosr cells prematurally differentiate into red blood cells in the placenta, due to prominent amounts of EPO, a cell-signaling protein molecule. The findings on the PDGF-B signaling pathway and EPO were gathered from experiments done on mice by researchers at UCLA. =====

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Those against embryonic stem cell research argue that the embryo is still a human being, and thus cells cannot be taken from a human life for research; these pro-life advocates argue that lives are being destroyed this way. They argue that the embryo is being murdered, for researchers may obtain stem cells by removing the outer layer of the blastocyst called the **trophectoderm**, at which point the cell mass can no longer develop into a human being. These same folks are against the practice of taking unused embryos from in-vitro fertilizations and taking stem cells from them, at which point researchers would destroy the embryo. Those who are for embryonic stem cell research argue for the brimming possibilities stem cells could bring, from curing diseases to increasing the rate of successful transplantations to curing paralysis. =====

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Still other scientists have mixed reactions about stem cell research. Tim McCaphrey, a professor at George Washington University, argues that it isn't practical to use stem cells, for if an embryonic stem cell is inserted into a human body, it will want to continue growing as an embryo and create another human being, instead of just creating the desired body part, such as a kidney or arm for example. =====

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In 2001, President George Bush increased federal funding for stem cell research. However, he limited taxpayer funding and also restricted funding for 21 previously established stem cell lines, putting researchers at a disadvantage for continuing previous research, as they lacked the funding. President Obama implemented a bill to increase funding in cell lines created in the private sector and in ones that already existed, unlike President Bush. Today, over one billion dollars are designated to stem cell research, and over 200 companies are devoted to this promising science. (3) =====

[|Stem Cell Controversy Today]

__Basics of Embryonic Development__
The human zygote goes through **indeterminate cleavage**, meaning that as the zygote goes through early divisions, each cell produced has the ability to develop into a complete embryo. This type of cleavage occurs only in deuterostomes, and it is a characteristic of the human zygote that explains why embryonic stem cells have such vast developmental versatilty. This type of cleavage is also what makes indentical twins possible. Protostomes, on the other hand, go through **determinate cleavage**, where the developmental fate of each embryonic cell produced by a division is determined early on.

There are three components to embryonic development: cell division, **cell differentiation**, and **morphogenesis**. As a cell goes through a series of mitotic divisions, it becomes a large,hollow ball of cells called a **blastocyst**. Next, the cells differentiate - they become specialized in structure and function. This is the stage in which a bone cell becomes a bone cell and a muscle cell becomes a muscle cell, for example. In morphogenesis, these newly differentiated cells are organized into tissues and organs depending on their type. This is why all organisms of a species have virtually the same body plan; all individuals' cells go through approximately the same paths during morphogenesis.

When cells go through morphogenesis, they arrange themselves into three germ layers: an inner **ectoderm**, a middle **mesoderm**, and an outer **endoderm**. Each of the three germ layers contains different types of cells, and each layer develops into different parts of the body. The ectoderm gives rise to the nervous system (neurons, spinal cord, and brain), the lens of the eyes, the epidermis, hair, and mammary glands.The mesoderm becomes the skeletal muscles, the skeleton, the skin dermis, connective tissues, the heart, blood, the kidney, and the spleen. The endoderm develops into the stomach, the colon, the liver, the pancreas, the urinary bladder, the lining of the urethra, and the epithelium of the trachea, the lungs, the pharynx, the thyroid and the parathyroid, and the intestines.



__REVIEW QUESTIONS__ a. transcription of the neighboring cells' RNA b. apoptasis of cells in the vicinity c. differentiation in the neighboring cells d. a signal transduction pathway invloving tyrosine-kinase e. a signal transduction pathway involving G-proteins
 * 1. Induction between cells causes which of the following?**

a. once the trophectoderm is removed from the outer layer of a blastocyst, the blastocyst can no longer develop into a human b. removing a trophectoderm from neural stem cells may cause brain damage c. inserting a trophectoderm into a blastocyst could impair embryonic development d. trophectoderms are produced by cloning embryonic stem cells e. a patient who receives stem cells with trophectoderms is at a high risk of rejecting the transplanted cells
 * 2. Why are trophectoderms a controversial aspect of stem cell research?**

a. determinate cleavage only occurs in prokaryotes and indeterminate cleavage only occurs in eukaryotes b. determinate cleavage dictates which cells will become somatic stem cells and indeterminate cleavage dictates which will remain gametic stem cells (oogonium and spermatagonium) c. determinate cleavage occurs only in gametic stem cells, whereas indeterminate cleavage occurs in all cells d. determinate cleavage produces cells with a determined fate, and indeterminate cleavage produces cells that can continue to develop and differentiate e. determinate cleavage occurs in deuterostomes, and indeterminate cleavage occurs in protostomes
 * 3. What is the difference between determinate and indeterminate cleavage?**

i. totipotent cells ii. pluripotent cells iii. multipotent cells a. i b. i and ii c. ii d. i and iii e. i, ii, and iii
 * 4. Freddy the embryo is five days old. At this point, what type of cells does he have?**

a. dendrite b. axon hillock c. nucleus d. soma e. axon a. humans are more likely to reject stem cells than other cells when undergoing a transplant b. when the outer layer of the blastocyst containing embryonic stem cells is removed, the embryo can no longer develop into a human being c. when the outer layer of the morula containing embryonic stem cells is removed, the embryo can no longer develop into a human being d. because stem cells can differentiate into anything, when implanted into a human body, they could form the wrong organ or desired structure, therefore causing major complications e. adult stem cells can interfere with adult somatic cell growth, division, and signaling.
 * 5. Which part of a neural stem cells expresses different genes at different times during development?**
 * 6. What is one argument against stem cell research?**

a. it creates too many cells, making it harder to isolate the small number needed in the first place b. it can only be done in a laboratory environment c. there is no difference between spontaneous and directed differentiation d. in plain culture, the stem cells only differentiate into one type of cell, making it less efficient e. in plain culture, the stem cells differentiate into a plethora or cell types, making it harder to isolate the desired type of cell
 * 7. What is one drawback of spontaneous differentiation?**

a. it provides the stem cells with nutrients b. it provides a haven where blood cells can grow, but not mature and differentiate into adult cells, thus preserving their status as stem cells c. it provides an safe area where the growth of blood stem cells is not inhibited or otherwise influenced by the growth and differentiate of other, somatic cells d. it provides the stem cells with the proper proteins to inhibit them from undergoing proper differentiation e. the stem cells in the placental niche act differently/fulfill a different duty than the stem cells in the umbilical niche
 * 8. What is the role of the “placental niche” in stem cell development?**

a. Stem cells' DNA is replicated one fewer time than a mature cell's DNA b. Mature cells' DNA is wrapped around histone proteins, but stem cells' DNA is not c. Mature cells' DNA coils upon itself, whereas DNA of a stem cell only coils once, around a histone protein d. There are no differences between the DNA of stem cells and mature cells e. Histone proteins only wrap around stem cell DNA
 * 9. What is the difference between the DNA of a stem cell and the DNA of a mature, differentiated cell?**

a. Most people's DNA sequences are closer to the DNA of an embryonic stem cell than the DNA sequence of another person who's ancestor's DNA has had many mutations and is too different to safely transplant. b. Embryonic stem cells aren't at a point in their development that they are tagged c. Embryonic stem cells exist in our bodies, so we view them as "self" d. Adult stem cells only have specific functions, so it is less likely that they would match the need of a person needing a transplant e. Embryonic stem cells can be altered in a lab setting to become adult stem cells
 * 10. Why is it better to transplant embryonic stem cells into a patient than to transplant adult stem cells of another person?**

Stem cell research is one of the fastest growing fields because of its potential to help millions of people with currently untreatable diseases. However, there are some controversies surrounding the use of stem cells for medical research. (20 points) a. Explain the mechanisms by which stem cells can become many types of cells. (10 points) b. Discuss some of the sources of controversy surrounding stem cell research. (10 points)
 * ESSAY QUESTION**

__Sources__

2.[|Neural Development] Figures outlining the steps of neural stem cell formation
3. [|Government Funding and Involvement with Stem Cells] 4. [|Current Research] A senator's point of view on stem cell research 5.[|Umbilical Cord Stem Cells] New research on stem cells from the umbilical cord 6. [|Cell Signaling in Blood stem cells] An article explaining the significance of the placental niche 7. [|Internet Science Room] A user-friendly guide to body plans 8. [|National Institute of Health] A solid overview of somatic and embryonic stem cells 9. [|Utah Genetics] A plethora of animations, articles, pictures, and interactive explorations: all about stem cells 10. [|Utah Teacher Resources] A branch of the wonderful University of Utah page with lesson plans about stem cells 11. [|Stem Cell DNA] An article regarding how stem cells reproduce 12. [|The Immortal DNA of Stem Cells] A news article describing the features of stem cell DNA 13. [|Transgenic Gene Therapy] An overview of how to create transgenic animals

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