The Power of STEM CELLS

by Jais Brar

As more research has been conducted in pursuit of new medical advances, stem cell therapy has emerged as a promising and hopeful treatment method for many conditions. In 2021 alone, the stem cell market was worth 77 billion HKD, and is continually growing at an exponential rate, it is estimated to surpass 246 billion HKD by 2030. (1) Stem cells can be used in numerous ways as they have the potential to develop into any cell found in the body. Unlike most cells that are only able to undergo a limited number of divisions before their death, stem cells can undergo an infinite number of divisions (2), making them one of the most unique scientific discoveries in the past 100 years.

This was followed by promising news, in 2012, stating that pluripotent stem cells could potentially be used to treat blindness. Human trials for this began in 2014, with Masayo Takahashi leading the study in treating age-related blindness and easing symptoms.(6) The inserted stem cells differentiated into retinal pigment epithelial cells, which are e damaged or lost in people with vision impairments, therefore improving vision and sight. Another way in which stem cells can be used in treating vision impairments is by collecting corneal limbal stem cells from a donor and using these to treat corneal damage. Although there are not cures for all of the sight related diseases, new remedies relating to optical issues such as glaucoma and wet macular degeneration, are being researched into extensively. (7)

Stem Cell Potencies

Stem cells all have the possibility of turning into specialized cells, however, within stem cells there are different levels of capabilities of transforming into different cell lineages. These include; totipotent, pluripotent, multipotent, oligopotent and unipotent, as shown in Figure 1.

The History of Stem Cells

Around 30 years ago, scientists discovered ways to obtain embryonic stem cells from early stage mice embryos. Biologists that studied these cells soon realized that the cells were pluripotent, meaning they have the potential to be converted into any adult body cell. Further laboratory experiments enabled scientists the ability to extract embryonic cells from humans and grow them in lab conditions. Prior to this, in the 1950s, the first stem cell transplant was given to nuclear researchers who had been exposed to radiation from cells found in the bone marrow. This procedure was carried out by Georges Mathé, a French oncologist.

Then later, in the 1960s, Ernest McCulloch and James Till gained new insight into blood cell formation through the discovery of haematopoietic stem cells. (3) This was done by injecting bone marrow cells into mice that had endured nuclear radiation. The cells were seen to develop into the three primary components of blood: red blood cells, white blood cells and platelets. Although these occurrences were rare,it demonstrated that differentiation was possible in bone marrow cells.(4)

Another major breakthrough in the stem cell world was the cloning of the infamous Dolly the sheep. Ian Wilmut and Alan Trounson, at Roslin Institute, managed to clone her using the DNA from an adult sheep’s mammary gland (found in the breast tissue), showing that if an adult cell was fused with an empty egg cell it would mirror the genetic makeup of the body it is being inserted into and replicate all tissues and organs, along with proving that the entire DNA of an adult was present in a single cell. (5) In around 1998, James Thomson and John Gearhart began to grow stem cells in the lab and in 2006, Shinya Yamanaka created induced pluripotent stem cells by injecting four key genes. Stem cells were increasingly used in medical therapy in the early 2000s, such as the first authorized trial on treating someone with a spinal cord injury with stem cells derived from embryos.

Totipotent Cells

Totipotency is the highest level of potency a stem cell can have. This means that they are able to differentiate into any cell, whether it be embryonic or adult. They can develop into over 200 different types of specialized cell in the body, making their differentiation potential optimal for medical use. Totipotent cells can be extracted from human zygotes, or zoospores, asexually reproductive structures found in algae and fungal species. The zygote is totipotent as it can evolve into any of the three germ layers; ectoderm (which forms the exoskeleton), the mesoderm (which forms the organs), and the endoderm (which forms the inner lining of organs).(9) Despite the fact that these cells fall into the most favorable category of stem cells, they are rarely used in scientific research as not only they are arduous to obtain but also go against various ethical guidelines. (10) As totipotent cells are derived from the first stage of formation of a fetus, obtaining them harms the blastocyst on the sixth or eighth day of development. This in turn destroys the embryo. However, as the embryos used in this practice are donated from IVF clinics and are deemed unwanted, it can be argued that it does not in fact breach any ethical regulations.

After approximately 4 days, the zygote grows into an embryo. Embryonic stem cells are stem cells obtained from the inner cell mass of a blastocyst, which is a human embryo between 3 to 5 days old and contains about 150 cells only. Pluripotent cells can progress into any of the three germ layers, as shown in Figure 2, but not into any extra-embryonic structures, such as the placenta. These types of stem cells are completely pluripotent as they have the potential to be specialized into any body cell and even undergo mitosis, enabling them to divide into larger quantities of stem cells. This trait, along with being easier to acquire, allows them to be greatly useful for medical practices, especially in regenerating organs, tissues and aiding in overcoming a disease with limited treatment availabilities. (10)

Unipotent stem cells are characterized by their narrow capabilities in cell differentiation. They are only adequate for one singular cell lineage, for example muscle cells only being able to evolve into mature muscle cells. (13) Unipotent cells are distinguished from non-stem cells by a few key characteristics, one of which is being able to self-renew. (14) This is the process in which stem cells can divide and reproduce asexually with the help of mitosis, the cells self-divide in their undifferentiated states, which allow them to be highly beneficial. (15)

Stem cells can also be induced, meaning they can be created in lab conditions. Induced pluripotent stem cells (iPS) can be derived from adult body cells and have been reprogrammed through inducing genes to make them pluripotent. Like many other scientific advances, these cells were first found in mice fibroblasts (a lineage of cells that are responsible for the production of connective tissue) in 2006 by Yamanaka and then later in 2007 they were first independently produced from human fibroblasts. iPS cells behave in similar ways to embryonic stem cells and hold a lot of the same characteristics, some of which include expression of Embryonic Stem cell markers, chromatin methylation patterns (methylation inhibits gene expression in cells by affecting chromatin structure. Chromatin is a mixture of DNA and special proteins, such as histones) (16), embryoid body formation (three-dimensional aggregates) (17) , pluripotency and many more.

Somatic cells can be reprogrammed into iPS cells by the transcription genes Oct4 (octamer-binding transcription factor 4, a molecular marker for germ cell tumors) (18), Sox2 (SRY-box 2, a marker for multipotential neural stem cells) (19), Klf4 (kruppel-like transcription factor, a protein coding gene) (20) and c-Myc (MYC proto-oncogene, BHLH transcription factor, a regulator of cellular metabolism and proliferation) (21). These factors, along with a few others,can reprogram adult somatic cells (any body cell that is not a gamete) and transdifferentiate them into neural stem cell like structures (22). iPS cells can be an excellent alternative to embryonic stem cells as they are comparatively less invasive, making them more ethical. They can also be especially useful in regenerative medicine (involved with regenerating tissues or organs), disease modeling and drug discovery. (23)

As mentioned previously, the most prominent attribute of stem cells is that they are able to differentiate into any desired cell. When a cell divides by mitosis, it forms two identical daughter cells and these cells can either: both remain as stem cells, both differentiate into new cells or have one remaining as a stem cell and the other differentiating . When both daughter cells either differentiate or remain as stem cells, it is called a symmetric division, whereas when they both carry out different processes this is known as asymmetric division. The chances of a symmetric division happening, 70%, is relatively high compared to those of an asymmetric division, 30%. This property allows the cells to retain their ability to perpetually divide as it ensures that stem cell levels are kept at a constant level, i.e. stem cells don’t deplete.

These types of cells have a lower differentiation potential compared to pluripotent cells. Multipotent cells are limited in their capacities, they can specialize into sub-cells in a specific cell lineage but cannot develop into any type of cell. An example of multipotent cells are hematopoietic cells, which can be found in bone marrow or in the blood from the umbilical cord. Hematopoietic cells have the ability to evolve into any blood cell but are unable to produce cells that are not blood cells. In recent years, scientists have located the presence of multipotent hematopoietic cells in the heart, which have the tendencies to develop into heart muscle of endothelial cells. These can be extremely helpful in treating blood cancers like leukemia. (12) Oligopotent cells, found within specific tissue e.g. the cornea , can self-renew and regenerate into more lineages within a particular type of cell. They can also form terminally differentiated cells of a specific tissue, meaning oligopotent cells no longer have the ability to undergo mitosis and proliferate. (13)

When it comes to the mechanics behind the specialization of stem cells scientists are still unsure as to what aids it since they are still relatively new. Producing mature neurons is pivotal to understanding the physiology of human neurons and glial cells and the pathology of neurological diseases, such as epilepsy. The cells differentiate into neural progenitor cells by embryoid body formation, then they are directed into specific neurons. These steps are all accomplished with the help of transcription factors.

Pancreatic β-cell helps in glucoregulation, when blood glucose levels are too high they produce insulin therefore the production and transplantation of these β-cells can treat diabetic patients. For this cells are induced into a definitive endoderm (one of the three germ layers) and then they further differentiate into pancreatic cells. (24) Pluripotent stem (iPS) cells can also be used in myogenic regeneration of skeletal muscle and cardiac muscle, along with hepatocyte differentiation (hepatocytes are parenchymal cells in the liver that are crucial in metabolic action, detoxification and protein synthesis) (25).

Medicinal application of stem cells

Since stem cells are so versatile, they can be used profusely in treating medical conditions. Some of the conditions include:

Tissue regeneration:

Prior to the discovery of pluripotent stem cells, patients with damaged organs or tissues had to wait extensive periods to receive a transplant but in present times scientists can use cell differentiation to grow organs and tissues to replace the organ.(26)The human skin has remarkable regenerative capabilities, especially with the epidermis (the outermost layer of skin) being able to continually regenerate. This is most helpful when treating severe burns and other chronic wounds. Plastic surgeons use stem cells extracted from beneath the skin surface to grow new skin tissue. This newly grown skin tissue is placed onto the open wound, allowing the skin to grow back, closing any exposed wounds. (27)

Cardiovascular disease treatment:

With ischemic heart disease being the leading cause of death in the world, it is essential that there are successful therapies to prevent myocardial infarctions (heart attacks). Scientists have found methods to insert stem cells into the cardiac tissue with a catheter to help regenerate the deteriorated tissue, improving the patient’s quality of life. (28)

Brain disease treatment:

Stem cells can be used to replace and regenerate impaired brain cells that cause neurological disorders, such as Parkinson’s and Alzheimer’s. Parkinson’s disease, for example, is caused by lowered levels of dopamine in the brain due to a loss of nerve cells in the substantia nigra (located within the midbrain).

(29) Stem cells can be directly placed in the brain where the damaged nerve cells are, where they regenerate into nerve cells and regulate dopamine levels, suppressing certain symptoms of the disease. Although this is not a definite cure for the disease it can help lessen the symptoms, and hopefully with more development can act as a permanent cure. (30)

Blood disease treatments:

Blood diseases, such as leukemia, multiple myeloma and lymphoma, can be a consequence of genetics, side effects of medication or due to a lack of particular nutrients. (31) The bone marrow produces all blood cells, thus by taking hematopoietic stem cells from the bone marrow or the umbilical cord can produce healthy red blood cells to carry oxygen and healthy white blood cells to fight the cancerous cells, infections and other pathogens. (32) In cases of hemophilia A, a blood disease caused by the lack of blood clotting factor VIII that causes excessive bleeding as the blood isn’t able to clot. Stem cells can differentiate into platelets to aid in blood clotting as a treatment for the disease. (33)

Conclusion

In conclusion, stem cells are exceedingly beneficial to the medical world due to their versatility. Although their use is controversial as they are derived from living organisms and can be seen as wasteful, the amount of effort and money that goes into the research and advancement of stem cells will in turn change the way we perceive them, and reveal how valuable stem cells are to humans.

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