Stem Cells

Research using stem cells is probably the most controversial area of scientific research today. The ethical controversy has resulted in delay of treatments. Stem Cells are so early in development; all uses are still experimental and will continue to be so for some time.

Researchers have since found new methods of acquiring stem cells that would not require the use of the initial controversial method. In fact the newer uncontroversial methods are proving better methods for obtaining stem cells.

Information here is to help explain as much about the subject matter as possible, to help with clarification. Topics explained will include:

1. Embryonic Stem Cells: Stem cells are embryonic or what is known as primitive cells. They are found in three to five day old embryonic blastocysts. They are not gotten by removing a fertilized ovum from a woman's body. (NIH, 2009)


2. Stem Cells vs. Mature Cells: There are three things that make stem cells different from regular somatic cells. They are able to replicate (divide) for long periods of time, they are able to turn into specialized cells (NIH, 2009) such as cells of the muscle tissue, brain, liver and heart (Klug, 2012) and they are unspecialized. Cells that have already differentiated (changed) into mature cells, a cell type in a tissue do not replicate indefinitely nor do they change into other cell types (Klug, 2012), and they are not unspecialized; they have very specific functions.


3. Adult Stem Cells: Adult stem cells are also called somatic stem cells because they are found among already differentiated cells in tissues and organs that are fully mature. They have been located in many different tissues such as brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis.(NIH, 2009)


4. Induced pluripotent stem cells (iPS): In very recent years, scientists have made several different stem cell types without the use of embryos. Induced pluripotent stem cells (iPS) are one of the most promising. They are made using human somatic cells as the source of pluripotent stem cell lines.


5. The Debate Over Stem Cells: To establish embryonic stem cell lines in the lab, that fact that early embryos are destroyed in the process disturbs some people. This debate raises the fundamental question of what makes a human being. The development of iPS stem cells from somatic cells has renewed the interest in stem cell research. Because these cells are developed from somatic cells and not embryos the ethical debate over their use is bypassed.


6. What Are Stem Cells Good For?: Research is still needed, but in time there will be many things Stem Cell treatments will be good for including; Regenerative Medicine, Understanding Cancers and Birth Defects, and Medication Screening and .


7. Missing Tumor Suppressor Genes: Dangers of NF2 or Cancers with Stem Cell treatments.

---

1. What are Embryonic Stem Cells?

Stem cells are embryonic or what is known as primitive cells. They are found in three to five day old embryonic blastocysts. At this stage of development, the blastocyst consists of 100-150 cells. Most of these cells develop into placental and supporting tissues for the embryo. The rest of these cells make up what is called the inner cell mass which will eventually develop into embryonic tissues. The inner cell mass consists of 30-40 pluripotent stem cells. In order to create stem cells that grow in cell culture dishes the inner cell mass is taken out which destroys the blastocyst at day 3 - 5 after fertilization.(Klug, 2012) The embryos are usually procured through in vitro fertilization centers where they are no longer needed and donated to research with full donor consent. They are not gotten by removing a fertilized ovum from a woman's body.(NIH, 2009)

2. What Makes Stem Cells Different From Other Cells?

There are three things that make stem cells. different from regular somatic cells. They are able to replicate (divide) for long periods of time, they are able to turn into specialized cells (NIH, 2009) such as cells of the muscle tissue, brain, liver and heart (Klug, 2012) and they are unspecialized.(NIH, 2009) Humans have about 200 different cell types in their adult bodies all of which are descended from stem cells.

There are different kinds of stem cells. Totipotent stem cells have the ability to develop into any mature kind of cell or tissue in the body. Pluripotent stem cells can develop into a smaller number of mature cell types. Contrast these abilities of stem cells with mature cells in the body. Cells that have already differentiated (changed) into a cell type in a tissue do not replicate indefinitely nor do they change into other cell types (Klug, 2012), and they are not unspecialized; they have very specific functions.

Several research teams in the past few years have isolated and learned how to culture pluripotent stem cells in culture dishes in the lab. These cells remain stem cells and grow indefinitely. But when scientists treat these pluripotent stem cells with different growth factors or hormones they differentiate or begin to change into cells that have the characteristics of neural, bone, kidney, liver, heart or pancreatic cells. (Klug, 2012)

3. What are Adult (Somatic) Stem Cells?

Adult stem cells are also called somatic stem cells because they are found among already differentiated cells in tissues and organs that are fully mature. Scientists are still investigating the origin of somatic stem cells. Somatic stems cells are thought to be undifferentiated cells (not matured into a specific cell type). They have been located in many different tissues such as brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis.(NIH, 2009)

Their role in these tissues is thought to be to differentiate into the tissue or organ they are in to repair damage to the tissue by dividing and to replace the damaged cells or to fight disease in these tissues.

Where are somatic stem cells found? They are in what scientists call a "stem cell niche" or specific area in the tissues and organs in which they are found. Some believe they comprise the outer layer of certain small blood vessels in organs or tissues. It is typical to find only a very small number of stem cells in tissues. Once somatic stem cells are removed from the body their ability to divide in the lab is limited. An active area of research is to figure out how to culture somatic stem cells in culture dishes for long periods of time so that many, many cells can be produced. In addition, figuring out how to make specific cell types from somatic stem cells in order to treat injury or disease is also very active area of research. (NIH, 2009) Indeed the whole subject of developmental molecular biology is fascinating as well.

4. Induced pluripotent stem cells (iPS)

In very recent years, scientists have made several different stem cell types without the use of embryos. Induced pluripotent stem cells (iPS) are one of the most promising. They are made using human somatic cells as the source of pluripotent stem cell lines.

To make iPS cells in the lab, scientists first isolated some somatic cells from tissue such as skin for example. Next the cells are infected with what is known as specially engineered or genetically programmed retroviruses. These retroviruses are pre-programmed to go into the cells and into the cell nucleus where the cell's DNA is and to integrate or fit into the cell's DNA according to the retrovirus's genetic instructions. In addition, the retrovirus has had several human genes added to them. When the retrovirus fits into the cell's DNA, these human genes are turned on, and the instructions they contain are carried out. The genes from the retrovirus are pre-programmed to tell the cell to make several proteins that carry instructions for turning adult somatic cells into pluripotent stem cells with the ability to divide indefinitely. These cells have been induced by retroviruses to become stem cells, so they are iPS cells. Sometimes cells that divide indefinitely in tissue culture dishes in the lab are called immortal. (Klug, 2012)

5. What Is the Debate Over Stem Cells?

To establish embryonic stem cell lines in the lab, that fact that early embryos are destroyed in the process disturbs some people. They believe that blastocysts which are pre-implantation embryos at day 3 - 5 after fertilization in the lab or in vitro are persons and therefore have rights. On the other side of the debate are people who believe that blastocysts are too primitive, having only 100 - 50 cells and not even implanted into the uterine wall yet, to have the status of a human being with rights. This debate raises the fundamental question of what makes a human being.

The development of iPS stem cells from somatic cells has renewed the interest in stem cell research. Because these cells are developed from somatic cells and not embryos the ethical debate over their use is bypassed. In addition to making the use of human embryos to create pluripotent stem cells obsolete, the development of iPS cells may become patient specific so they can be used for transplantation without the problem of immune system rejection. Because the initial somatic cells would be harvested from the patient in the first place; they would not be rejected.

6. What Are Stem Cells Good For?

Research is still needed, but in time there will be many things Stem Cell treatments will be good for including:

• Regenerative Medicine
• Understanding Cancers and Birth Defects
• Medication Screening

Regenerative Medicine

A possible treatment for stem cells under Regenerative Medicine would be the regeneration of bone using cells gotten from bone marrow called stromal stem cells or skeletal stem cells. Another example is the repairing of the heart muscle following a heart attack with cardiac muscle cells. (Klug, 2012)

Cell based therapies is probably the most important prospective use of human stem cells where the generation of cells and tissues would be relatively easy. Today, we rely on donated organs and tissues to replace damaged or destroyed tissue. But unfortunately the need for donated organs and tissues outnumbers the supply. Stem cells offer a renewable supply of cells and tissues that could be used to treat many degenerative diseases by directing them to differentiate into a specific cell type. Some of the diseases that could be treated include Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis. For example, it may become conceivable to produce healthy heart muscle cells in the lab.(NIH, 2009)

Understanding Cancers and Birth Defects

The use of embryonic stem cells in the lab to study the development and differentiation of cells involved in human development could be very important. We already know that this process involves turning genes on and off. Cancer and birth defects are due to abnormal cell division and differentiation. If there were a more complete understanding of genetic and molecular processes that controlled human development it might provide insight into how cancers and birth defects arise. This in turn could suggest new therapies.

Medication Screening

Another use of human stem cells is medication screening. New medications might be assayed for safety using pluripotent cell lines as the source of differentiated cells. The availability of pluripotent cell lines could mean the availability of a wider range of cell types than is currently in use.

7. Missing Tumor Suppressor Gene

NF2 is not a Cancer in that the tumors which grow as result of NF2 are generally Benign (Noncancerous), with only a chance they can become Malignant (Cancerous). However, they are similar in that NF2 like Cancers where tumors are always Malignant, are the result of repression of a tumor suppressor gene.(Kasinski, 2011)

Cell death is a normal event necessary to eliminate unwanted and potentially dangerous cells, but a missing tumor suppressor gene slows down or might stop cell death and promote tumor development.

Since encouragement of cell death is needed when a tumor suppressor gene is not working properly, stem cell treatments to fix damage done by tumors, it would be dangerous in that these treatments are more likely to result in tumor growth instead of the desired results of healing.(Garcia, 2010)

8. Glossary

• adult stem cells: undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues.
• blastocyst: In humans, its formation begins 5 days after fertilization during the germinal stage of development. It possesses an inner cell mass (ICM) which subsequently forms the embryo. The outer layer of cells of the blastocyst are called the trophoblast. This layer surrounds the inner cell mass and a fluid-filled cavity known as the blastocoel. The trophoblast gives rise to the placenta.
• cellular differentiation: process by which a less specialized cell becomes a more specialized cell type.(Quizlet, 2014)
• fertilization: the fusion of gametes to initiate the development of a new individual organism. In animals, the process involves the fusion of an ovum with a sperm, which eventually leads to the development of an embryo.
• induced pluripotent stem cells (iPS): are a type of pluripotent stem cell that can be generated directly from adult cells. The iPSC technology was pioneered by Shinya Yamanaka's lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes could convert adult cells to pluripotent stem cells.[1] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent."
• inner cell mass: the mass of cells inside the primordial embryo that will eventually give rise to the definitive structures of the fetus. This structure forms in the earliest steps of development, before implantation into the endometrium of the uterus has occurred.
• in vitro fertilization (IVF): is a process by which an egg is fertilized by sperm outside the body: in vitro. IVF is a major treatment for infertility when other methods of assisted reproductive technology have failed.
• pluripotent: a stem cell that has the potential to differentiate into any of the three germ layers: endoderm (interior stomach lining, gastrointestinal tract, the lungs), mesoderm (muscle, bone, blood, urogenital), or ectoderm (epidermal tissues and nervous system).
• regenerative medicine: is the "process of replacing or regenerating human cells, tissues or organs to restore or establish normal function". This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue and/or by stimulating the body's own repair mechanisms to heal previously irreparable tissues or organs.
• retrovirus: a single-stranded RNA virus that stores its nucleic acid in the form of an mRNA genome (including the 5' cap and 3' PolyA tail) and targets a host cell as an obligate parasite.
• stem cells: are undifferentiated biological cells that can differentiate into specialized cells and can divide (through mitosis) to produce more stem cells. They are found in multicellular organisms.
• stem cell niche: refers to a microenvironment where stem cells are found.
• totipotent: the ability of a single cell to divide and produce all of the differentiated cells in an organism.
• transplant rejection: occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

References

1. Klug, William S., Michael R. Cummings, Charlotte A. Spencer, and Michael A. Palladino. "Stem Cell Wars." In Concepts of Genetics, 10th ed., 468 - 469. Boston: Pearson, 2012.
2. Stem Cell Basics. Bethesda, MD: National Institutes of Health, 2009. Accessed: February 14, 2014. http://stemcells.nih.gov/info/basics/Pages/Default.aspx
3. Quizlet. "Unit 1: Biochemistry & Cells (Cell Division)." Last modified 2014. http://quizlet.com/24771399/unit-1-biochemistry-cells-cell-division-flash-cards
4. Kasinski, A. L., & Slack, F. J. (2011). MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nature Reviews Cancer, 11(12), 849-864. http://www.nature.com/nrc/journal/v11/n12/abs/nrc3166.html
5. Garcia-Fernandez, M., Kissel, H., Brown, S., Gorenc, T., Schile, A. J., Rafii, S., ... & Steller, H. (2010). Sept4/ARTS is required for stem cell apoptosis and tumor suppression. Genes & development, 24(20), 2282-2293. http://genesdev.cshlp.org/content/24/20/2282.full