Stem cells and their potential use for medical treatments
Embryonic stem cells vs somatic stem cells
Stem cells are undifferentiated cells of the human body with the potential to become one or more cell types upon differentiation. Stem cells have two major categories which they can be divided into: embryonic stem cells and somatic stem cells.
Embryonic stem cells are stem cells which are formed after the first divisions of the zygote. Approximately 5 days after fertilisation, the dividing zygote reaches a stage during which it is called the blastocyst. The blastocyst consists of an outer layer of cells known as the trophoblast and an inner mass of cells called the inner cell mass. It is the inner cell mass which consists of cells. In further development of the embryo, the trophoblast goes on to become the placenta, while the inner cell mass starts to differentiate and goes on to form the foetus.
Somatic stem cells are stem cells which are found in tissues of a human. There are only a few tissues which contain somatic stem cells. There are, however, no tissues at all which contain embryonic stem cells. Moreover, the list of tissues where somatic stem cells have been observed is increasing with ongoing research. For now, somatic stem cells have been observed in bone marrow, peripheral blood, brain, spinal cord, dental pulp, blood vessels, skeletal muscle, the epithelia of the skin and digestive system, cornea, retina, liver, and pancreas.
Both types of stem cells also differ in potency. Potency is the term given to the number of different cell types the stem cells can form upon differentiation. There are 3 types of potency: unipotent (stem cells which only form one cell type upon differentiation), pluripotent (stem cells which can form multiple cell types upon differentiation), and totipotent (stem cells which can from any cell type upon differentiation). Somatic stem cells are mostly unipotent and can sometimes be pluripotent; while, embryonic stem cells are totipotent, which gives them incredible potential for use in therapy.
Differentiation and induction
Stem cells naturally differentiate to become a specific cell type. Despite common misconception, the DNA sequence is the same in all of the somatic (all cells apart from germ cells) cells of an organism. Hence the process of differentiation doesn’t change the DNA sequence of the stem cells. The process is epigenetically regulated (genes for specific proteins are activated or shut down by editing chromatin [the environment around the DNA]). Despite the process being natural, it can also be prompted and directed by certain chemical or biological agents. This becomes very useful in therapy when stem cells need to be differentiated into a specific desired cell type required to treat the patient.
There is a very useful model which helps to understand differentiation called Waddington’s landscape (figure 1). This model was created by Conrad Hal Waddington in 1957 to summarise the epigenetically controlled differentiation of stem cells (Wikipedia, 2021).
The model shows a peak (like a hill) with troughs at the bottom. At the peak one can see a totipotent (or in this case pluripotent) stem cell, which is represented by a ball. Each trough at the bottom of the peak represents a different cell type. The process of differentiation itself is represented by the ball rolling down the hill and stopping in one of the troughs. Natural differentiation cannot be controlled and hence can be represented as a random push of the ball (stem cell) down the hill at a random time, making it end up in a random trough (as a random cell type). However, differentiation can be prompted and directed by chemical and biological agents. This can be represented as a purposeful push of the ball (stem cell) down the hill, making it end up in a chosen trough (as a chosen cell type).
Such ‘pushes down the hill’ are useful for therapeutical stem cell applications, however, if a patient is treated with stem cells from a different organism, it can cause problems from minor immune responses to rejection of the differentiated stem cells. To prevent rejection of the cells it is safest to introduce genetically identical cells (cells with exact same DNA sequence as the patient’s cells) back into their body. To achieve this one needs to obtain stem cells with the exact same genome as that of the patient. For somatic stem cells, this is easier as one can extract the patient’s somatic stem cells from their body, then either prompt differentiation or promote cell division (depending on whether the patient requires more stem cells or more differentiated cells) [both are usually done using chemical and biological agents], and reinsert the cells back into the patient’s body. However, for embryonic stem cells, this is much harder as one needs to create an embryo with the exact same genome as that of the patient. This is nearly impossible to do via creating an embryo through sexual reproduction due to the crossing over of chromosomes and their different combinations in germ cells. To overcome this great difficulty, scientists have created ‘cheat codes’ to create genetically identical (to the patient) embryonic stem cells.
There are two main ‘cheat codes’ for this process. The first involves creating an embryo, the second involves reprogramming already differentiated cells. The first method involves creating an embryo with the same DNA sequence as that of the patient. This is achieved through the removal of the nucleus from an egg cell and its replacement with the nucleus of a cell from the patient’s body. Once the egg cell’s nucleus is replaced by the nucleus of a somatic cell, the epigenetic marks on the DNA of the patient’s somatic cell are reset under the influence of egg cell cytoplasmic factors. This leads to the formation of a zygote, which then starts dividing, forming an embryo. Once the embryo reaches the blastocyst stage, embryonic stem cells can be extracted from the inner cell mass and differentiated into the target cell type required to treat the patient. The extracted embryonic stem cells are genetically identical to the patient’s somatic cells as the DNA sequence is identical in both. This method is known as somatic cell nuclear transfer.
The second method involves the epigenetic reprogramming of one’s somatic cells to return them to their totipotent state. This reprogramming is called induction and can be represented on Waddington’s landscape by the ball (cell) being rolled up the hill (reverse of differentiation) from a trough (a specific cell type) due to an acting force. This acting force represents chemical and biological agents which promote the resetting of the epigenetic marks in a cell and its return to a totipotent state. An example of biological agents used for induction of stem cells are the Yamanaka factors. The genes coding for these proteins were discovered in the mouse genome by Shinya Yamanaka in 2006 (Nobel Prize, 2021). Yamanaka factors are expressed to a great extent in totipotent and pluripotent stem cells, but are expressed to a very low degree in somatic cells. This observation led Shinya Yamanaka to believe that an overexpression of these factors in somatic cells could lead to their epigenetic reprogramming and return to a totipotent or pluripotent state. Indeed, his hypothesis was correct and was later shown to work in humans as well. The Yamanaka factors are as follows: (Oct3/4, Sox2, Klf4, c-Myc), they are responsible for signalling cells to maintain a totipotent/pluripotent state by restricting epigenetic marks and changes to chromatin. If Yamanaka factors are overexpressed in a cell, the cell ‘rolls up Waddington’s landscape’ and returns to a totipotent state, resetting epigenetic marks, but keeping its DNA sequence the same. This allows for the induction of genetically identical (to the patient’s somatic cells) stem cells from a patient’s somatic cells. These cells can then be differentiated into the desired cell type.
Both of these methods reduce the risk of cell rejection or other immune responses, increasing treatments’ safety and reliability.
Ongoing and potential treatments
Stem cells are already being used therapeutically, however, for now, stem cell treatments are in their early stages and hence clinical trials are still being conducted for most of the treatments, as opposed to the treatments being widely used in conventional medicine. According to an extensive analytical study performed by nature (taking into account 177 stem cell clinical trials), the leading countries in stem cell clinical trials by percentage of world-wide studies conducted are as follows: USA (36%), France (15%), China (12%), Japan (9%), UK (6%), Israel (6%), Germany (4%), South Korea (2%), Australia (2%), Pakistan (2%), Taiwan (2%), Brazil (1%), India (1%), Italy (1%), Netherlands (1%), Iran (1%). (Nature, 2020)
Furthermore, the same study analysed the most common disease types stem cell treatments are being developed for (by percentage of all trials). These are as follows: ophthalmic diseases (24.4%), cardiovascular diseases (14.5%), neurological disorders (13.0%), metabolic diseases (6.9%), genetic syndromes (6.1%), none (4.5%), mental disorders (4.0%), neoplasms (4.0%), reproductive and urogenital diseases (3.8%), defects of the immune system (2.3%), hematologic disorders (2.3%), otorhinolaryngologic diseases (0.8%), other (13.4%). This clearly shows the wide range of disease which could be treated by stem cells and the number of countries working on treatments to develop stem cells’ high potential. (Nature, 2020)
For now, few diseases are treated by stem cells outside of clinical trials. These are mostly blood and immune system disorders and some cancers. The stem cell treatments in use are mainly cell transplantations. This is because, for now, stem cell treatments have not proven themselves to be safe or reliable. Nevertheless, with advancements in the field, existing treatments will be perfected and new ones will be developed, with stem cell treatments possibly becoming the main treatment method for many genetic or degenerative disorders. This leaves me to believe that stem cells have a colossal potential to become a widely used treatment and to be excited to see new advancements being constantly made in this very new field.
Bibliography
A Closer Look At Stem Cells, n.d. Many clinics offering stem cell treatments make claims that are not supported by a current understanding of science. [Online]
Available at: https://www.closerlookatstemcells.org/stem-cells-medicine/nine-things-to-know-about-stem-cell-treatments/
Britannica, 2020. Somatic cell nuclear transfer. [Online]
Available at: https://www.britannica.com/science/somatic-cell-nuclear-transfer
Nature, 2008. Yamanaka factors critically regulate the developmental signalling network in mouse embryonic stem cells. [Online]
Available at: https://www.nature.com/articles/cr2008309#:~:text=Yamanaka%20factors%20(Oct3%2F4%2C,necessary%20for%20ES%20cell%20pluripotency.
Nature, 2020. Global trends in clinical trials involving pluripotent stem cells: a systematic multi-database analysis. [Online]
Available at: https://www.nature.com/articles/s41536-020-00100-4
Nobel Prize, 2021. Shinya Yamanaka Facts. [Online]
Available at: https://www.nobelprize.org/prizes/medicine/2012/yamanaka/facts/
Wikipedia, 2021. C. H. Waddington. [Online]
Available at: https://en.m.wikipedia.org/wiki/C._H._Waddington
Wikipedia, 2021. Shinya Yamanaka. [Online]
Available at: https://en.m.wikipedia.org/wiki/Shinya_Yamanaka
