Many incurable health problems are characterized by the death of cells that cannot regenerate or repair themselves upon damage or injury. For example, cardiac muscle cells die in heart attack, nerve cells perish in the brain during a stroke, and insulin-producing cells vanish in diabetes. Unfortunately, these cells are incapable of regeneration, leading to irreversible damage. Laboratory scientists are developing potential solutions to replace these cells. 

Stem cell scientists are studying the use of stem cells to produce functional cells that could be transplanted into patients to treat and potentially reverse the damage. Remarkably, scientists can take skin or blood cells and turn them into cells that can become any cell in the body, known as an induced pluripotent stem cells (iPSCs). These characteristics make iPSCs an accessible and versatile source for generating cells to replace those lost due to disease or damage. iPSCs can be made from anyone, and consequently could theoretically be used to make individual batches of replacement cells for every patient. However, such a process is inefficient and expensive. Scientists are working to make universal donor stem cells that could ideally be transplanted into anyone without immune rejection.

A key requirement for cell transplantation is an immune match between the donor and recipient to avoid immune rejection, just like organ transplants. The key factors governing this tissue compatibility are called the human leukocyte antigens (HLAs). They are expressed on the cell’s surface and enable the immune system to distinguish self from non-self, acting as a personal cell “ID card.” If HLAs between the donor cells are mismatched to the recipient, the immune system will identify the transplanted cells as foreign and attack and kill them. Such immune rejection can be life-threatening to the recipient. The probability of a perfect HLA match is about 1 in 100,000 between two unrelated individuals, representing a fundamental challenge for any transplantations, including cell-based therapies. 

A Universal Stem Cell Bank

To solve this problem, scientists have proposed several different strategies. In one proposed strategy, scientists are attempting to isolate and “bank,” or store, iPSCs that would be immunologically compatible with many different people. In another, researchers are using genetic approaches to engineer stem cells that would be accepted by any recipient.  

The Global Alliance for iPSC Therapies (GAiT) was established to create an international registry of clinical grade iPSCs. “This is similar to how the international bone marrow donor registry has worked, where the stem cells of a donor are available to recipients living in different countries,” says Associate Professor Ngaire Elwood, Director of the BMDI Cord Blood Bank in Melbourne, Australia, and a collaborator of Global Alliance for iPSC Therapies. Accordingly, banks like GAiT enable.” iPSC-based therapies by providing a resource to find compatible transplantable materials.

Researchers in some countries are undertaking efforts to establish iPSC lines that would be compatible with the majority of the population. In general, there is less genetic diversity in the Japanese population than in other countries and theoretically only a small number of iPSC lines would be needed to be HLA-compatible with a large proportion of the population. Nobel Laureate Shinya Yamanaka has led an effort at the Kyoto University Center for iPSC Research and Application to bank these compatible stem cell lines. So far, they have created 27 iPSC lines, which in principle, would be compatible with 40 percent of the Japanese population. Similarly, Cambridge University, UK scientists predict that as few as 150 selected donors would cover at least 90 percent of the UK population.

Genetic differences, however, may still cause immune rejection. In these cases, recipients would need to take immunosuppressant drugs long-term, which impairs their ability to fight off infections. An alternative transplant strategy is to create genetically modified stem cells that can completely hide from the immune system of anyone, so-called “universal” stem cells.

Creating Universal Stem Cells
Given that HLA mismatching is the chief barrier for cell transplantation, scientists have used gene-editing tools to inactivate key HLA genes of iPSCs. These bioengineered iPSCs, designated “universal” stem cells, are able to evade immune rejection and represent a unique approach to developing transplantable cells for genetically diverse populations. Inactivating the HLA genes in universal stem cells, however, does have a potential risk. HLA genes are required for the elimination of cancer cells and there is concern that should these universal cells become cancerous, that they could grow unchecked by the recipient’s immune system.

A potential solution to mitigate the risk is to include a mechanism that would kill the universal cells if needed. Andras Nagy’s team in Toronto, Canada is a leading the way in developing a “cell suicide system” to make universal stem cells safer. In this system, stem cells are engineered to contain a suicide switch that could be activated when the cells start showing any abnormalities, such as uncontrolled growth. As a result, problematic cells would be killed before they form tumors. 

“Universal cells require significant genetic manipulation, including a suicide switch, this approach will have a more difficult time being approved by the regulators for routine clinical use,” says Ngaire, who has 13 years of experience running a cell manufacturing facility licensed by the Therapeutic Goods Administrations in Australia.  

Either by banking iPS cells from a variety of donors or by genetically manipulating them, these approaches to using stem cells are laying the foundation to develop new transplantation treatments for incurable diseases. Like all currently available treatments, the balance of the benefits versus risks is the key consideration towards successful clinical translation. 

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Blog by guest contributor S.C. Jacky Sun, PhD candidate in the labs of Ed Stanley and Andrew Elefanty at the Murdoch Children’s Research Institute, Melbourne.