In theory, it’s possible to produce all types of human cells from pluripotent stem cells in the laboratory. During the past 20 years scientist have succeeded in producing increasingly functional cells. However, the usage of these in treatment of human disease is still only being developed.
Tissue stem cells are a safer alternative for stem cell treatments compared to pluripotent stem cells. Yet, tissue stem cells are difficult to obtain and often also difficult to culture in the laboratory. Some tissue stem cells have however already been used for long times in treatments of different diseases and continued research can result in new types of tissue stem cells being used for therapy.
Bone marrow transplants have been used successfully for treatments of different blood diseases for more than 40 years and have significantly improved the prognosis of many previously incurable diseases. Human blood stem cells reside in the bone marrow inside virtually all bones of the body. The renewal capacity of the bone marrow is astonishing with blood stem cells producing around 500 billion new blood cells, that is red and white blood cells and platelets, every day. Thus, a small amount of transplanted bone marrow is able to effectively replace blood cells, that are defective or have been lost due to disease.
Bone marrow transplants are frequently used in the treatment of lukemia, in other words blood cancer, and other severe forms of cancer. The white blood cells of the lukemia patient are destroyed by chemotherapy or radiation therapy, leading also to the destruction of healthy blood cells. The patient receives a bone marrow transplant containing blood stem cells, that replace the sick and destroyed blood cells. The bone marrow usually originates from a suitable anonymous donor found through the international stem cell registry. Sometimes, a bone marrow transplant from a relative can also be used. A bone marrow donation will not even momentarily affect the ability of the donor’s bone marrow to produce new blood cells due to the very small amount of the donated bone marrow. It’s also possible to retrieve blood stem cells from the circulation, placental blood or cord blood. In these cases, the amount of blood stem cells is much smaller. Many leukemia patients, especially children, recover fully thanks to stem cell transplants. Blood stem cells are also used to treat other blood diseases and immune deficiencies.
The skin contains two types of stem cells that renew the skin and the body hair. Human skin renews approximately once a month when the stem cells residing in the deep layer of the skin gradually produce new skin cells and old skin cells shed off. In the 1970’s, scientists learned to culture human skin cells in the laboratory, leading to the development of skin transplant methods. It however took many years before the role of skin stem cells in the success of skin transplants was understood; the skin was able to renew due to the stem cells present in the transplant.
During a skin transplant, the patient’s own healthy skin from other parts of the body is usually used since the body rarely rejects its own skin transplant. The transplant can be taken from many parts of the body but usually the site is chosen so that the skin resembles that of the injured area as closely as possible. Nowadays it’s possible to grow new skin in the laboratory for months of time and once the skin is transplanted it’s able to renew the patient’s skin for decades without any signs of cancer-causing changes. Skin transplants are used a lot for burn injuries but also for treatment of wounds that are difficult to heal or result from a large surgery. In 2017, a team of Italian scientists was able fort the first time to perform a near whole-body skin transplantation using transplants that originated from the patient’s own gene-corrected skin cells. They were thereby able to save the life of the patient, a young boy, who suffered from a life-threatening skin disease.
In 2015 the EU approved a stem cell based therapy for treating eye injuries of the cornea. The cornea is normally renewed by its own stem cells called limbal stem cells. If the limbal stem cells are injured, for example following a chemical accident, it can lead to blindness. Corneal transplants, that have been grown from limbal stem cells in the laboratory, can be used to repair this kind of injury.
Retinis pigmentosa is a condition where the retinas of the eyes gradually are destroyed, leading to loss of vision. Using stem cells, it’s possible to generate cells that can support the retina and halt the progression of the disease, possibly even leading to partial restoration of lost vision. Both embryonic stem cells and iPS cells have been used in experimental treatments with promising outcome. The amount of transplanted cells is small and the cells are well differentiated, which diminishes the risk of the transplanted cells causing tumours, thereby increasing the safety of the treatment.
So-called mesenchymal stem cells (MSC) originate from the bone marrow and can generate bone, cartilage and fat cells. Mesenchymal stromal cells, that are isolated from connective or fat tissue, are also sometimes referred to as MSC. There are thus different kinds of cells that are called MSC and their ability to generate bone or cartilage tissue depends on their origin as well as handling of them in the laboratory. MSC’s have not been shown to be able to generate other specialized cells apart from bone, cartilage and fat cells.
Scientists are looking into the possibilities to use MSC’s in treatments of bone and cartilage injuries. In the laboratory, MSC’s are able to generate cartilage tissue, but attempts to get these cells to repair arthritis of the knees in humans have had conflicting outcome. These treatments are not approved for example by the US Food and Drug Administration, FDA, or by the European Medicines Agency, EMA. However, the EMA has approved treatments that rely on cartilage cells, not MSC’s, for arthritis treatments.
MSC’s are also known to be able to reduce inflammation and much of the benefits that have been reported for experimental treatments using MSC’s are thought to be a result of the anti-inflammatory, not cartilage-renewing, properties of MSC’s. In Finland, the usage of adipose tissue transplants in treatments for perianal fistulas associated with Crohn’s disease was recently approved. Mesenchymal stromal cells in the transplants have an evident local anti-inflammatory effect. The possibility to use MSC’s in other serious inflammatory diseases is being investigated.
It is not possible to transplant pluripotent stem cells, that is embryonic stem cells or iPS cells, as such to humans since they will generate tumours instead of functional tissue. During the past 20 years it has however been possible to produce for example nerve, heart, intestinal or pancreatic cells and many other types of cells from embryonic stem cells and iPS cells. Thus, we are now approaching a time when it’s possible to start testing treatments using cells, that originate from pluripotent stem cells, on people. The reason for the slow development is difficulties in achieving sufficient differentiation or functionality, which is needed for a successful outcome. Another reason for the development taking time is safety, which must be guaranteed. A single tumour-generating cell in the transplant could have devastating effects.
Stem cells are being differentiated into tissue cells for many different treatment purposes, which are associated with various challenges. In addition to the examples mentioned here, pluripotent stem cell based therapy could also be useful in the treatment of many other diseases in the future.
For a cell therapy to succeed, it is often crucial that the transplanted cells start to function as part of a clearly defined anatomical structure. This is the case for the treatment of many different diseases and the treatment of Parkinson’s disease with dopamine producing nerve cells is a good example of this. In animal experiments, it’s been shown that it’s possible to get the cells to start functioning in the right part of the brain. Promising results have also been obtained when human fetal cortical cells have been injected into the brain of Parkinson’s patients. An advantage of this treatment is the relatively small amount of cells needed to achieve the desired result. On the other hand, it’s a big challenge to get the cells to function in the correct place of the brain. It’s likely that nerve cells originating from embryonic stem cells and possibly also from iPS cells can be introduced in experimental treatments of Parkinson’s disease in the upcoming few years.
Cell therapy that relies on the usage of stem cells is also a promising future alternative treatment option for diabetes, which results from insulin deficiency. Development of treatments is eased by the fact that the insulin-producing cells do not have to be transplanted to the site where they would normally function, in other words to the pancreas. Pancreatic cells from deceased organ donors have been used as transplants already for decades. The treated patients have usually been type 1 diabetics at the same undergoing kidney transplantation for progressed diabetic kidney disease. In these treatments, the cells have usually been injected into the liver, where they have remained functional for years, resulting in the patients no longer needing insulin injections. Cells from organ donors are only available for a small number of special patients.
Stem cells differentiated into pancreatic islets, the insulin producing units of the pancreas, could solve this problem. To achieve the desired outcome of the treatment, it’s enough to get the cells to function with sufficient blood supply somewhere in the body. Thus, a simple procedure where a cell transplant is inserted under the skin could work. Pancreatic islets produced from stem cells function well when transplanted to animals and are able to keep the blood sugar of the animal on a normal level. Development of these therapies for humans has already proceeded to clinical trials. But definite evidence of their functionality is still lacking.
Bone marrow and the blood stem cells within it, has been used in stem cell therapy with good results already for decades. With blood stem cell therapy, it’s possible to treat both inherited diseases, such as immunodeficiencies and haemoglobin disorders, and diseases that develop later in life, such as blood cancer. In contrast to many other tissues, the blood and all blood cells can be rebuilt from the same “seeds”, meaning from blood stem cells.
Transplant rejection is still a challenge for stem cell treatments and can have serious consequences. Thus, scientists are actively investigating whether it would be possible to produce blood stem cells for example from the patient’s own skin cells. Another challenge is developing laboratory conditions, that allow for producing and storing large amounts of stem cells. Since blood stem cells have been used for long times within health care, they are likely pioneers also for applying gene therapy and gene modification methods for human treatment. The first gene therapy substance containing stem cells has been granted market approval in 2016 and patient trials relying on the usage of the CRISPR “gene scissors” method have already begun.
The use of organoids, originally developed as suitable models for research, can also lead to new treatment opportunities. Since organoids are able to self-organize cells similarly to tissues, it’s possible to produce large amounts of cells that both renew the tissue and keep up its functions, using organoids. In principle, organoids can be used as a sort of living band-aid, which simultaneously grows and covers the injured area while taking over its function. Scientists are already testing if it’s possible to repair wounds of the intestine with the help of intestinal organoids injected into the gut.
Organoids from new tissues are being developed all the time, but the possibility to use these as transplants depends on how well they represent their tissue of origin and therefore also target tissue. Moreover, organs are built up of many different tissues and it’s unlikely that laboratory conditions allowing for simultaneous co-culture of all required tissue types will be developed. In the future, organoid methods are likely to increasingly be combined with the development of artificial organs so that attempts are made for example to grow living tissue on top of 3D printed organ models in multiple rounds.
Genome editing refers to modifications of DNA. With different genome editing methods it’s possible for example to correct disease causing gene errors and remove or add parts of genes to cells grown in the laboratory for research purposes. In 2020, Emmanuelle Charpentier and Jennifer Doudna received the Nobel prize in chemistry for developing the CRISPR genome editing method, which was published in 2012. Compared to previous methods, CRISPR is a more effective and precise genome editing method. Thanks to CRISPR, researchers today know the function of an increasing number of genes and understand the consequences of many gene errors on cellular function.
CRISPR genome editing is used frequently for studying disease mechanisms. Scientists either induce a disease-causing gene error to cells or correct an excising error and study how this influences the functions of the cells. By combining CRISPR genome editing and iPS technology, it’s nowadays possible to clarify specific disease mechanisms in cell models that are relevant for the disease in question and made from the patient’s own cells.
The combination of stem cell technology and genome editing in theory allows for ideal possibilities to treat severe inherited diseases that today lack a cure. The path form basic research on cells and mice to patient care is however long. It’s nonetheless likely that we in the future will see new treatment options and that the first real breakthroughs will pave way for extensive new development.
Treatment of inherited disease with stem cells can be conducted using stem cells form a healthy donor that does not carry the disease-causing gene mutation. Alternatively, it’s possible to use the patient’s own stem cells, in which the gene error has been corrected with genome editing or gene transfer.
The first clinical study using genome edited stem cells in attempts to treat humans was initiated in 2019. In the trail, a severe haemoglobin disorder is treated with genome editing. At the end of 2020 the trial had so far been successful and the patients, who were earlier dependent on blood transfusions, had been able to go without additional blood transfusions for 1-2 years.
When scientists learned to culture embryonic stem cells 20 years ago, this also led to some unrealistic expectations by the public. Stem cell enthusiasts also gave exaggerated promises of treatments coming in the near future. The development from basic research to new treatments takes a very long time. This is particularly notable when it comes to the stem cells with the highest plasticity, that is the pluripotent embryonic stem cells and iPS cells.
It is important to understand that pluripotent stem cells as such lack any value for human therapy. If they are transferred to the human body they will form tumours, teratomas, in which a mix of different tissues grow. Scientists must first learn to handle these cells so that they differentiate in a desired direction and at the same time lose their ability to make tumours.
It’s possible to achieve safe and effective stem cell treatments only by using the right types of cells. The cells cannot be able to make tumours or unwanted cell types and they must have the capacity to generate the specialized cells that are needed. If these requirements are not met, the treatment could cause more harm than benefit for the patients. Unfortunately, in some countries there are clinics that perform procedures where most often the patient’s own, unsuitable, cells are used. Stem cell tourism has become a problem where patients are charged large amounts of money for treatments that are ineffective and sometimes even dangerous.
People who oppose the use of stem cells often condemn research performed with embryonic stem cells because the cells are derived from destroyed human embryos, even though these embryos are left over from infertility treatments and would in any case be destroyed. The ethical problems related to usage of embryonic stem cells can be avoided by using iPS cells.
Some stem cell research methods also cause new ethical dilemmas. Examples are brain organoids or human-animal cell hybrids. Brain organoids, stem cell derived mini organs in which nerve cells build up structures which resemble brain parts, are very important for research on for example neurological diseases or brain tumours. Some people have asked if it’s possible that brain organoids could achieve some sort of consciousness. Human nerve cells have also been transplanted into mouse brains for the purpose of developing stem cell treatments. Although it’s easy to imagine that brain organoids or human nerve cells within mouse brains could be able to think and feel like humans, the reality is very far from this. As methods develop in the future, these considerations can however become justified.
The same ethical principles that concern other treatments also apply to stem cell treatments. All medical activity is driven by the notion that the treatment cannot be more harmful than the treated disease. All new inventions are accompanied by uncertainties and the probability of risks has to be evaluated in relation to the benefits of the treatment. Sometimes it can be difficult to estimate the risks and it can for example be especially difficult to know how long a new stem cell treatment should be followed up for possible risks to be revealed.
The combination of gene therapy or genome editing with stem cell therapy causes new ethical considerations since these treatments come with risks of genetic changes that could for examples increase the probability of cancer. Inherited genome modifications, that is, gene modifications that could be passed on to the next generation, where for example sex cell producing stem cells are manipulated, are forbidden in most countries and for example completely in the EU. Human cloning is also clearly forbidden in most countries, whereas animal cloning is considered one way to save endangered species from extinction.