Stem Cells in Regenerative Medicine

From our skin to our liver, stem cells are what allows the human body to heal after injuries or to grow. However, many cells don’t have the ability to regenerate after an injury, so in 2007, when Japanese researcher Shinya Yamanaka discovered induced pluripotent stem cells (iPSC), this provided a new hope for regenerative medicine and organ donations.

Yet, while this discovery sparked a new interest in stem cell therapy and earned Yamanaka the Nobel Prize, scientists are still exploring the potential risks and benefits of stem cells, as the ability of stem cells to grow indefinitely has raised concerns over the possibility of induced pluripotent stem cells turning into cancerous cells.

But could scientists overcome this problem? How could stem cell therapy be used in regenerative medicine?

The basics of stem cells

There are three fundamental properties of stem cells. First, the cell must be able to give rise to specialized cell types like muscle cells or neurons. Second, stem cells must be unspecialized, meaning they cannot perform a specific function like a specialized cell, and third, they must be able to self-renew and divide for long periods of time, unlike muscle cells and blood cells that don’t normally divide.

Our bodies contain stem cells, called somatic (adult) stem cells, which function to repair and replace damaged tissues. These stem cells are typically considered multipotent, which means that they can differentiate into multiple specialized cell types, although more restricted than pluripotent stem cells, which can differentiate into all of the cell types in the body with the exception of extraembryonic tissue, such as the placenta. This includes embryonic stem cells, which are able to differentiate into all of the cell types of the body since these cells come from the inner cell mass of 5 day old clumps of cells in human embryos, called blastocysts.

What are iPS cells?

However, this has sparked controversy among the public as many people are opposed to the idea of using human embryos for medical research. Because of this controversy, when in 2007, Japanese researcher Shinya Yamanaka discovered that by adding a combination of four transcription factors, skin fibroblast cells could be turned back into pluripotent stem cells capable of differentiating into any cell in the body, this was a promising discovery for the future of medicine.

Scientists hoped that these induced pluripotent stem cells (iPS cells), as they were called, would be capable of transforming into healthy blood cells to treat leukemia, turn into neurons to treat neurological disorders, or produce insulin to treat diabetes, while also reducing the risk of immune rejection.

How stem cells could treat neurological disorders

One promising development for stem cell therapy is to treat neurological disorders and injuries, including Alzheimer’s Disease, which is an irreversible and progressive brain disorder that causes memory and thinking skills to deteriorate and affects around 50 million people worldwide, and Parkinson’s Disease, which is a common progressive nervous disorder that affects movement, often causing tremors.

Currently, there are no cures for Alzheimer’s Disease, but scientists are working on a stem cell treatment to regrow neurons. Because Alzheimer’s is a neurodegenerative disease, a potential treatment may be to transplant stem cells into patients with Alzheimer’s to help regenerate new and healthy neurons.

However, according to EuroStemCell, a concern is the complexity of this treatment, as the stem cells would need to travel to multiple areas of the brain, produce the right numbers and types of neural cells, and form working connections with other neurons. Nevertheless, current studies with mice have shown benefits with this procedure, such as when scientists at the University of Michigan transplanted human neural stem cells into mice with Alzheimer’s Disease. Mice that had been treated using stem cells had a significant improvement in recognition, spatial memory, and learning. 

In addition, scientists at the Harvard Stem Cell Institute have been using stem cells to study the amyloid-ß protein produced in Alzheimer’s patients, which are sticky plaques that build up and eventually kill brain cells, leading to Alzheimer’s. By turning the skin cells of Alzheimer’s patients into brain cells through iPSC technology, scientists can study the proteins produced by those cells, since most Alzheimer’s research today is focused on preventing the formation of amyloid-ß plaques.

This is a significant discovery for drug development, as by using iPS cells, scientists will be able to test promising drugs and treatments on different types of brain cells, rather than unrelated cells. Stem cells may also be useful for treating injuries as well, as in 2002, researchers found that when a rat with a spinal cord injury paralyzing the lower body and hind limbs was injected with stem cells at the site of the injury, its movements and body functions significantly improved after just a week from the treatment.

Stem cells could also promote axon growth in spinal cord injuries, as it was discovered that neural stem cells can secrete neurotrophic factors, which are peptides that support the growth and development of neurons, and this could help the growth of damaged axons. However, current research on the use of stem cells in neurological diseases is still in early stages, and there are many barriers to overcome before stem cells will become a viable treatment in treating incurable or progressive neurological diseases.

How stem cells could treat heart disease

Currently, there are more than 114,000 people on the waiting list for organ transplants, and everyday, 20 people die due to the lack of organs available for transplant. Yet, what if we could use stem cells to help this issue?

As it turns out, stem cells may hold the key to organ transplants, as the ability of stem cells to regenerate could help replace tissues damaged by disease and reduce the number of organ transplants. For example, during a heart attack, the blood flow to the heart is blocked, causing the heart tissue to be starved of oxygen, and this causes the heart cells to die. After the heart attack, the oxygen-starved heart cells don’t completely heal, and instead, it forms a scar. But recently, scientists have been using stem cells to repair the heart after a heart attack by injecting stem cells into the heart to grow into new heart tissue. In a study published in The Lancet, 17 heart attack patients were injected with stem cells, and after a year, the scar tissue on the heart had shrunk on 50%.

While this is a significant improvement in helping heart attack patients, it’s not without its risks. As with most stem cell treatments, one significant barrier is the ability of the injected stem cells to integrate with the existing stem cells to form crucial connections. This is particularly important in the heart, as the heart has an electrical system that is in charge of the heart rhythm, and if the injected stem cells can’t communicate with the electrical system, this can cause abnormal heart rhythms called arrhythmias. Treatments using adult stem cells have had mediocre success because most of the cells died shortly after transplantation, but current studies transplanting heart tissue grown using embryonic stem cells and iPS cells have had much greater success.

Can stem cells be used to grow organs?

While growing entire organs is still far too complicated for stem cells, scientists can use stem cells to create organoids, which are miniature three-dimensional tissue cultures that can model the complexities and behaviors of organs.

In fact, a team of researchers at the University of Michigan Medical School managed to use stem cells to create three-dimensional miniature lungs that were then transplanted into mice. Another team from the National Institute for Physiological Sciences in Japan injected mouse stem cells into rat blastocysts, and when the blastocysts developed into fetuses, it was found that ⅔ of the rats had a functional pair of kidneys grown from mouse stem cells.

However, stem cell research is still far from growing entire organs, scientists are working on creating viable kidneys from diseased kidneys. This is done by decellularizing the diseased organ, which leaves the extracellular matrix scaffold that will guide the growth of the new cells. Then, the scaffold is seeded with stem cells, which will repopulate the scaffold with new cells, and this kidney can be transplanted into a patient. It was found that the repopulated kidney was able to clear metabolites, reabsorb nutrients, and produce urine in rats, so this method may serve as a new hope for those waiting for an organ donation. 

How stem cells are used in drug development

The organs and organoids grown from stem cells also serve another purpose – to help in drug development. Organoids are able to model the functions and interactions of tissues within an organ, so they can be used to study diseases and test for drugs.

When Shinya Yamanaka and his team first discovered iPS cells, scientists expected these stem cells to revolutionize medical treatments. However, iPS cells have become an even more important tool in biotechnology as they are useful for screening drugs and modelling diseases. For example, Stephen Minger and his team at GE Healthcare screened for toxicity using stem cells, and found that the stem cells were affected by the toxic compounds. Similarly, stem cells could be used to screen for potential drugs. In addition, fibroblast cells could be taken from patients with a specific disease, and turned back into stem cells using iPSC technology, then redifferentiated into cells specific to the disease, such as motor neuron cells.

According to Harvard Stem Cell Institute, “…Instead of being tested on brain cell types affected by Alzheimer’s disease, these compounds are often first screened with non-brain cells or random collections of brain cells. The result is that the vast majority of the compounds are thrown out in these early screening rounds due to a lack of potency. This screening process may be causing the premature disregard of some of the most promising future drugs because the compounds are not being tested on diseased cells.”

In conclusion, since stem cells can be differentiated into specialized cells from patients with a specific disease, they have been used by pharmaceutical companies to test for toxicity or screen for potential drugs.

“The result is that the vast majority of the compounds are thrown out in these early screening rounds due to a lack of potency. This screening process may be causing the premature disregard of some of the most promising future drugs because the compounds are not being tested on diseased cells.”

Harvard Stem Cell Institute

Could iPS cells turn into cancer?

However, despite the benefits stem cells have, there are potential risks as well. In particular, one concern with iPS cells is the possibility of these cells turning into cancerous cells, since stem cells have the ability to regenerate forever, and this can lead to the acquisition of random mutations that can cause cancer. In addition, when somatic cells from the patient are turned into iPS cells, scientists generally use the transcription factors Oct4 (Pou5f1), Sox2, cMyc, and Klf4, but when the transcription factors Oct4, Sox2, and NANOG (OSN) were expressed in cancer patients, it was associated with a higher risk of resistance to treatment for lethal cancers.

This may be due to epigenetic and genomic instability that may be present in iPS cells, although it was found that the iPS cells were able to maintain tumor suppressor methylation patterns from the original cell. In a study by Yamaguchi et. al., it was found that iPS cells derived from somatic cells with a chromosome instability increased the risk of the cells turning into cancer, as these cells formed an embryonal carcinoma-like structure, so the oncogenic potential of the iPS cell may be determined by the parent cell, rather than the iPS cell itself.

To overcome these potential issues, scientists have developed methods for preventing cancer growth in iPS cells, such as by adding the transcription factor p53, which is a tumor suppressor gene that can prevent mutations and regulate DNA repair, and this prevents unregulated cell growth that often leads to cancer.

Why is embryonic stem cell research so controversial?

Yet, one of the main controversies in stem cell research are embryonic stem cells, which are pluripotent stem cells derived from human embryos at the blastocyst stage, which is around 3-5 days old. Most of the embryonic stem cells used in research come from leftover embryos in in-vitro fertilization (IVF) clinics, since IVF procedures often involve fertilizing dozens of eggs and implanting the best ones, leaving many leftover embryos. Because the extraction of the stem cells involves destroying the embryo, many people are against this type of research since they believe that life begins at the moment of conception.

In 1995, the Dickey-Wicker Amendment was passed, prohibiting the use of federal funds for the creation or destruction of human embryos in research. However, scientifically, embryos only begin developing a nervous system until 14 days after conception, and a functional nervous system is only present after 6 months of gestation, so at the blastocyst stage, embryos are not capable of any mental life.

Michael Gazzaniga, a professor of psychology at the University of California, Santa Barbara, illustrates this developmental stage of the embryo’s nervous system as he states, “If a grown adult had suffered massive brain damage, reducing the brain to this level of development, the patient would be considered brain dead and a candidate for organ donation. Society has defined the point at which an inadequately functioning brain no longer deserves moral status.” Nevertheless, embryonic stem cells have been the subject of controversial debate, from the media to politics.

“If a grown adult had suffered massive brain damage, reducing the brain to this level of development, the patient would be considered brain dead and a candidate for organ donation. Society has defined the point at which an inadequately functioning brain no longer deserves moral status.”

Michael Gazzaniga, Professor of Psychology at University of California, Santa Barbara

Nevertheless, stem cells have a huge potential for the future of regenerative medicine

Since the discovery of stem cells and iPS cells, they have provided a new hope for curing diseases that are currently incurable, such as Alzheimer’s Disease, which affects 10% of people aged 65 and up.

In addition, stem cells have the potential to help the 114,000 people currently on the waitlist for an organ transplant, as regenerative medicine and stem cell therapy may one day allow scientists to inject healthy stem cells to replace diseased cells, reducing the need for organ transplants.

In drug development, stem cells have improved the efficiency of drug development by screening for toxicity and potential drug leads, which could prevent dangerous drugs from making it to the market. However, stem cells aren’t without its flaws: Many people fear that iPS cells have the potential to become cancerous, and the ethics of using embryonic stem cells have been widely debated in the media and in politics. Nevertheless, there’s no doubt that stem cells are a powerful discovery that could transform millions of lives worldwide.

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