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Printable Organs! (?)
In 2013, scientists at Scotland's Heriot-Watt University developed a 3D printer that can produce multiple living human embryonic stem cells. This might make it possible to print complete organs.
Since years, researchers have been investigating the use of stem cells in treating incurable diseases. Stem cell research has brought some success but has also raised a few ethical issues. For the successful use of stem cells in medicine, there are certain challenges to overcome. Their potency which is a determinant of their ability to differentiate into various stem cell types, limits their widespread use in medicine.
Perhaps, the biggest challenge in stem cell therapy is the availability of donor cells and the risks involved in transplants. In this Buzzle article, we will be discussing the types of stem cells and their applications in different branches of medicine, as well as some important findings and statistics in the field of stem cell research.
History
Though stem cell research is looked at as a modern study that can revolutionize medical science, early research related to stem cells can be traced to the 1960s.

It was then that Joseph Altman and Gopal Das came up with the evidences of neurogenesis in adults, which is a stem cell activity in the human brain.

The bone marrow transplant between two siblings to cure severe combined immunodeficiency marked the first success in the research on stem cells.

This was followed by the discovery of haematopoietic stem cells in human cord blood in the year 1978.

In 1997, a direct testimonial of cancer stem cells was brought about when leukemia was shown to evolve from haematopoietic stem cells.
In 2006, some English scientists created the first artificial liver cells with the help of the umbilical cord blood stem cells.

In January 2007, scientists at the Wake Forest University said that they had found a new type of stem cells present in the amniotic fluid, with a potential to substitute for embryonic stem cells.

In June that year, experiments were conducted on mice which led to the discovery that normal skin cells could be programmed to reach the embryonic state. In the same month, the first primate stem cell line was created by scientist Shoukhrat Mitalipov.

Mario Capecchi, Martin Evans, and Oliver Smithies won the Nobel Prize for Physiology or Medicine in 2007, for their work on embryonic stem cells in mice.
In 2008, scientists at the Advanced Cell Technology cloned human embryos to generate embryonic stem cells.

In the same year, the first human embryonic stem cells were created without destroying the embryo, by Robert Lanza and his associates at Advanced Cell Technology and UCSF.

In 2011, a research team led by Inbar Friedrich Ben-Nun developed the first stem cells from endangered species.

Stem cell research continues. It has the potential to cause a far-reaching change in the stem cell theory and greatly affect fields of health and medicine, thus impacting life.
Research on Stem Cell Types
Stem cells are found in most multicellular organisms. These cells can regenerate themselves by mitosis and differentiation. Those in mammals can be classified as embryonic stem cells found in blastocysts and adult stem cells found in adult tissues.

Cell culture can be used to grow and transform the stem cells into specialized cells. Apart from being able to renew on their own, stem cells can differentiate into various types of cells in the human body. This capacity of the cells is known as their potency.

Multipotent stem cells can produce cells of a closely related group. That means, their ability to differentiate is limited. Examples of multipotent cells include adult stem cells and cord blood stem cells. Those in the brain can produce different neural cells. Haematopoietic cells can give rise to different blood cells. They are considered as multipotent. Cells in the bone marrow are multipotent as they can produce all types of blood cells.

Multipotent stem cells perform the important function of replenishing the diseased and aged cells in the body throughout life, thus acting as the body's wear and tear system. These cells are of help in transplants, wherein they are isolated and made to develop into the desired cell types.
Neural cells can develop into nerve cells. If they can be isolated from adult or fetal brain tissue, they can be of use in treating brain and spinal injuries.

An adult stem cell is a cell that is found in a developed living being. Adult stem cells can create a cell like themselves as well as more differentiated cells. Mostly, they are multipotent. These cells have shown success in treating blood or bone cancers.
Multipotent and unipotent stem cells
Recent research on multipotent cells shows that they may be able to produce distinct types of cells, which negates the previous conception that they can be used in only those tissues from which they were isolated.

The ability of stem cells from one tissue to generate specialized cells from another tissue is termed as stem cell plasticity. It can prove to be a boon in stem cell therapy.

As multipotent stem cells are found in and can be isolated from tissues of adult animals, they don't have to be extracted from the fetus, unlike other types of stem cells.
A research published by Wiley-Liss showed that multipotent stem-like cells exist in the olfactory mucosa and they can be used for autologous transplantation therapies and for cellular studies of disease.

Unipotent stem cells can produce just one cell type. Its potential to differentiate is the least. As they can renew themselves, they are of use in transplants. On differentiation, they produce a specific stem cell. Examples of unipotent cells include those found in the epithelium. These stem cells in the skin can be allowed to differentiate and produce skin cells that can be used in transplants in case of burns. However, it can take many weeks for the skin to develop from stem cells.

Unipotent cells are not of use when a tissue is damaged and multiple cell types have to be generated.
Pluripotent cells are true stem cells. They can differentiate into almost any cell in the body. This potential is limited to the embryonic stage of development. The blastocyst formed after fertilization contains an inner cell mass that consists of pluripotent cells which are responsible for creating most cells and tissues in the body.

These cells can be isolated from the blastocysts from excess embryos produced during in-vitro fertilization, or from aborted fetuses. They can also be extracted from a certain type of tumor that occurs in a fetus.

As pluripotent cells can give rise to multiple cell types, they can be of help in treating various diseases. They can be made to differentiate into various types of cells to be used for experiments.

It has not been concluded whether pluripotent stem cells are present in adults.
Totipotent and pluripotent stem cells
Researchers from Sanford-Burnham Medical Research Institute in La Jolla, California experimented on using pluripotent stem cells in the treatment for hair loss. In the study led by Alexey Terskikh, PhD, associate professor in the Development, Aging and Regeneration Program at Sanford-Burnham, human pluripotent cells were used for hair growth. The stem cells were made to form dermal papilla cells, which on being transplanted into mice, generated hair growth in them.

Induced pluripotent stem cells (iPSCs) are those which are derived from the skin or blood cells of adults and genetically reprogrammed to an embryonic stem cell-like state.

These cells share many characteristics with pluripotent cells. It is not exactly known if there are clinical differences between these and embryonic stem cells.

iPSCs in humans can generate cells of all three germ layers.
A recent report from Medical News Today says that researchers from the Salk Institute for Biological Studies in La Jolla, California have described how they grew healthy NK immune cells from gene-edited stem cells of an SCID patient. According to them, it may be possible to implant the edited cells back into the patient to generate a new immune system. The process includes reversion of the patient's cells into iPSCs, correcting the fault in them through genetic editing, and making them produce NK cells. SCID, an incurable autoimmune disease may find a cure if this potential of stem cells is successfully tapped.

Totipotent cells are produced from the fusion of the egg and sperm cells. During the first few divisions that a fertilized egg undergoes, it produces totipotent cells. They can give rise to any cell type and can replicate indefinitely without losing their potency. As they can develop into any type of cell, they are of great use in gene and cell therapy and in transplants and replacement of diseased cells.
Embryonic Stem Cell Research
Embryonic stem cells are cell cultures that are derived from the epiblast tissue of the inner cell mass of a blastocyst, an embryo that is 4-5 days old. Human embryonic stem cells need the basic fibroblast growth factor.

Gail Martin, Matthew Kaufman and Martin Evans discovered the mouse embryonic stem cells. It was Gail Martin who coined the term 'embryonic stem cell'.

In 1998, James Thomson brought about the first human embryonic stem cell line.

Embryonic stem cells are supposed to be of great use in the treatments for nervous system disorders.
Embryonic cells are totipotent. They require specific signals for their desired differentiation. Their injection into the human body may result in their differentiating into different types of cells. This may lead to teratoma, meaning a tumor. Moreover, their transplant has a risk of getting rejected by the human body.

There has been some research in the field of embryonic cells but no proven treatments have been devised till date.

In January 2008, researchers were able to develop the human embryonic stem cells without destroying the embryo.

In a recent research funded by Arthritis Research UK, it was demonstrated how embryonic stem cells can be used to generate cartilage in rats. Cartilage cells are produced from precursor cells called chondroprogenitors. The researchers generated precursor cells from human embryonic stem cells and implanted them into the damaged cartilage in rats. It led to cartilage repair. This study is a ray of hope for arthritis patients.
Stem Cells in Disease Treatment
Stem cells can be used in treating diseases by way of stem cell transplant. If embryonic stem cells are made to differentiate to form cells of the desired type, they can then be used to replace the damaged cells in the patient's body. This method may be able to treat brain or spinal cord injuries and other neurological problems by using stem cells to replace the damaged neurons. If stem cells can be used to generate insulin-producing cells, they can serve as a treatment for diabetes. If used to create heart muscle cells, damage after a heart attack could be repaired.
Umbilical Cord Stem Cells
Cord cells are hematopoietic and not pluripotent, which means they can differentiate to form only blood cells and not any other. So their future use can apply to treating blood disorders.

However, cord tissue contains mesenchymal stem cells. They are multipotent stromal cells which can differentiate to form cells of the bone, muscle, and cartilage. It may be possible to use these in treating various diseases in animals.

A segment of the umbilical cord is stored in the frozen form in cord blood banks. Chances are that stem cells are extracted from the cord tissue to be used for disease treatment.
Umbilical Cord Stem Cells
According to the World Marrow Donor Association and European Group on Ethics in Science and New Technologies, the possibility of one's cord blood cells being of use for regenerative purposes is hypothetical.

In 2005, researchers at Kingston University in England claimed to have discovered a new type of stem cell which they called cord-blood-derived embryonic-like stem cells (CBEs). These cells were derived from umbilical cord blood, and according to the researchers, their ability to differentiate was greater than that of adult stem cells.

In 2006, researchers at Newcastle University, England created the first artificial liver cells using umbilical cord blood stem cells.
Public cord blood banking is encouraged over private banking, as public banking is free of cost, makes the stem cells available to anyone in need, and increases their availability, as opposed to private banking which is costly and the chances of being able to use one's own stem cells for disease treatment are less.

It has been demonstrated that stem cells can be used to adjust immune response in patients with an autoimmune disease. A stem cell educator can be used to change the behavior of the human immune cells by placing them close to stem cells.
Stem cell educator
In the stem cell educator therapy, cord blood-derived multipotent stem cells (CB-SCs) are isolated from human cord blood. Lymphocytes from the blood of a diabetes type I patient are fed to the educator. On coming in contact with the CB-SCs, they are 'educated' and can be returned for circulation.
Diabetes
The combined effort of researchers from the Diabetes Research Institute (DRI) and Dr. Lola Reid, an expert in liver development from the University of North Carolina, has led to the discovery of a new line of stem cells. These cells are found in the biliary tree in the body, and are pancreatic precursor cells.

If they can be programed to form islets and transplanted to diabetics, they will help regulate blood sugar levels in them.

In 2009, Yong Zhao and his associates conducted an animal experiment which showed that diabetes type I caused by an autoimmune process could be reversed with the use of cord blood-derived multipotent cells.

In 2012, a successful human clinical trial was conducted to treat type I diabetes with cell educator therapy using cord blood-derived multipotent stem cells.
Blindness
A report from The Telegraph suggests that stem cell transplant can be used in treating progressive vision loss. In a study at Jules Stein Eye Institute in Los Angeles, funded by Advanced Cell Technology, it was demonstrated that embryonic stem cells could be used to regenerate retinal pigment epithelium cells.

They were transplanted to patients with age-related macular degeneration (AMD), who showed marked improvement in their eyesight.
Nervous System Disorders
Neurogenesis results from cells that are possibly the remnants of stems cells that existed during brain development in the fetus. They can form neurons and glia, and are hence called neural stem cells. Neurons are generated only in some regions of the brain. However, there are chances of these cells being of use in replacing those lost due to degenerative diseases or injuries.

Researchers are identifying growth factors used by the brain as they could be used to reduce brain damage and to activate stem cells to repair the damage caused.

In the 1970s, cells from the substantia nigra of the fetal tissue of a mouse were transplanted into a rat. The cells were found to develop into mature dopamine neurons. Later, it was found that this transplant could reverse Parkinson's-like symptoms in rats and monkeys.

In two clinical trials funded by NIH, tissue from aborted fetuses was transplanted into the striatum of Parkinson's disease patients. While some patients showed improvement, many showed side effects. In some patients, their immune system did not accept the transplant.
Cardiac Repair
Stem cells may be of use in regenerating damaged myocardium due to heart attacks or other cardiovascular diseases. Various types of stem cells have been used in research to gauge their utility in successfully regenerating myocardial tissue. The procedure involves risks and there are challenges in ensuring the delivery of stem cells to the right site.

Embryonic stem cells were transplanted into ischemically injured myocardium in rats. They differentiated to form normal myocardial cells.

Transplants of skeletal myoblasts in rats and humans showed the ability to repair scar tissue damage and improve left ventricular function.

In 2001, Jackson, et.al. showed that stem cells derived from the bone marrow of a mouse could be used to generate cardiac muscle cells and endothelial cells, thus improving the survival rates after heart attack.

The multipotency of mesenchymal stem cells and their ability to differentiate into cells like cardiac myocytes makes these stem cells a good candidate for use in cardiac repair. They have been shown to increase myocardial function and capillary formation.

Cardiac stem cells have a higher potential of use in autologous stem cell therapy. The National Heart, Lung, and Blood Institute will be funding clinical trials to demonstrate the use of cardiac stem cells for regeneration of myocardial tissue.

Research is still on to demonstrate the use of endothelial progenitor cells to regenerate blood vessels and myocardium.
In Dentistry
In 2003, Dr. Songtao Shi of NIH discovered a source of adult stem cells in children's primary teeth.

David Mooney and his associates at Harvard's Wyss Institute have been able to use stem cells in regrowing teeth in rats. They have devised a technique that uses a low-power laser to make stem cells form dentin. In the experiment, tooth decay was introduced in the molars of rats. Then adult stem cells were applied to the pulp of the tooth, a laser was used to stimulate growth factors, and the teeth were sealed. In a few weeks, dentin was found to have started growing back. The results of their study have been published in the journal Science Translational Medicine. Mooney says this method of regenerating teeth rather than replacing them would be an important advancement in dentistry.

A research led by Igor Adameyko of the Karolinska Institutet in Sweden, discovered the presence of stem cells in the nerves of the teeth. It was found that during embryonic development, some glial cells become mesenchymal stem cells, which can then differentiate to form osteoblasts in the outer regions of the tooth pulp and form new dentin.

According to Adameyko, their findings have brought out the fact that stem cells are found in peripheral nerves, and that the multipotent stem cells in these nerves play a role in tissue formation and healing.
Birth Defects
According to Joseph Yanai, director of the Ross Laboratory for Studies in Neural Birth Defects at the Hebrew University-Hadassah Medical School, in Jerusalem, stem cell therapies are helpful to treat birth defects when the mechanism of damage is not fully understood. He says that if neural stem cells are used, they act as little doctors that can diagnose the defect and differentiate into the desired cell type to repair it.

Scientists have used stem cells in treating neural birth defects in mice. The research was conducted at the Hebrew University-Hadassah Medical School.

If the factors that trigger the multiplication and differentiation of stem cells are understood, we might be able to use stem cells for the prevention and reversal of birth defects.

When stem cells are derived from an individual who is genetically different from the patient, the transplant can lead to immunological rejection. To overcome this challenge, researchers will have to find a way to isolate stem cells from the patient's own body, to program them to function as stem cells, and then transplant them into the patient's blood.
Stem Cell Transplants
Here is a graphical representation of the three ways in which stem cells can be used in transplants. The first image shows the use of induced pluripotent cells for transplants. The second graphic shows the use of adult bone marrow cells for tissue development or transplant. The third image represents the use of embryonic stem cells to form specialized cells.
Somatic cells
As you see in the image above, somatic cells are genetically reprogrammed to form induced pluripotent stem cells. The stem cells obtained on gene correction are made to differentiate into the desired types of stem cells to be used for transplant.
Bone marrow transplant
Adult stem cells from the bone marrow can be used for transplant. They are multipotent, and can be used to generate different types of blood cells. Bone marrow transplants are used to replace damaged bone marrow with healthy cells. In autologous bone marrow transplant, stem cells from one's own body are extracted and returned to the body to generate healthy blood cells. In allogeneic bone marrow transplants, cells from a donor's body (genetically matching) are transferred to the patient's body. Preserved umbilical cord blood cells may also be used.
Pluripotent stem cells
Pluripotent cells extracted from a blastocyst, being pluripotent, can differentiate to form any cell type. The specialized cells thus obtained can be used for transplants, as shown above.
Stem Cells in Drug Discovery
As human stem cells can be made to differentiate in an artificial environment to form various specialized cells, they are of use in the discovery of drugs. They can be used for study in pharmacology and biotechnology.

Cells derived from tumors in animals or humans can be used to test their reaction to compounds.

The effectivity and toxicity of newly developed drugs can be tested on animals. But considering the cost and ethical issues involved, in vitro testing that stem cells allow is more beneficial.

To test a drug for chronic toxicity, the cells that it is being tested on, should have a long life. For it to be tested on all cell types, the cells should be available. As embryonic stem cells can differentiate into different cell types and for long periods, these constraints in drug testing are almost eliminated.

By deriving stem cells from different organisms, the efficacy of a drug can be tested across species.

Using the induced pluripotent stem cell (iPSC) technology, new cellular models can be created with varying degrees of susceptibility and resistance to drugs.
Ethics
Production of embryonic cells requires the destruction of an embryo. An embryo holds the potential of a human life. If made to be in the womb, it can give birth to a new life. For creating the embryonic stem cell line, a human embryo has to be destroyed and this destruction could mean depriving a human being of his right to live.

The factor that outweighs the ethical wrongs in the destruction of an embryo is the application of stem cells in cell therapies.

Some are of the view that since embryos are not humans, destroying them for medical use is not unethical. They also argue in favor of stem cell research saying that there is some percentage of zygotes, which do not implant and are wasted, which makes it a better option to use embryos for obtaining stem cells.

Using adult stem cells is a good alternative as it does not involve the destruction of embryos or sacrificing a potential human life.

However, embryonic stem cells are superior in many ways to adult stem cells. They divide rapidly, have a greater plasticity, and can be used to treat a wider range of diseases.
Stem cell research looks promising but there are many obstacles to be overcome; some medical, some ethical. With embryonic cells, it is about saving a life at the cost of a potential one. With adult stem cells, transplants are not always feasible. The biggest potential of stem cells is tissue generation, which can serve as the most effective treatment against several diseases. Will research in stem cells bring us this success?