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Blood stem cells: the pioneers of stem cell research

Blood stem cells were the first stem cells to be identified. Their discovery in the 1960s marked the beginning of stem cell research. Today, researchers continue to learn from blood stem cells, and are still identifying new ways to use them in the clinic. 

Introduction to blood stem cells

The analysis of healthy blood of a 115-year-old woman in 2014 showed that majority of her blood cells were derived from only two HSCs.

Our blood is composed of different cell types, which perform specific tasks. For example, red blood cells (erythrocytes) transport oxygen and white blood cells (leukocytes) defend the body from infections. Specialised blood cells do not live very long, so the body needs to replace them continuously. Blood stem cells replenish the cells of the blood system. 

Blood stem cells are also known as haematopoietic stem cells (HSCs). HSCs reside in the bone marrow in a specialised environment (their ‘niche). Like other stem cells, they can self-renew, or copy themselves, but also give rise to any type of mature blood cells. 

Cell division and differentiation of HSCs are tightly controlled by the body. This is to ensure the proper number of each type of blood cell. Blood cell production also needs to be responsive to increased demand for certain cell types when an emergency occurs, such as infection or blood loss occurs. The behaviour of HSCs is controlled by a network of signals within the body: both from the blood system itself, and other parts of the body.  

 

Current uses

HSCs are mainly used to treat blood disorders. They can also be helpful in treatment of solid tumours or autoimmune disorders.  

The European Society for Blood and Bone Marrow Transplantation (EBMT) reported in 2021 that more than 40,000 patients are treated with HSC transplant in Europe each year. More than half of transplantations are autologous. This means patient’s own HSCs are collected, preserved, and transplanted back to the same patient. The other option is an allogenic transplantation where the patient receives HSCs from another person (family member or unrelated donor).   

HSCs reside in the bone marrow. The first method of isolation of HSCs for transplantation was to take a bone marrow biopsy, which would contain HSCs in the sample. (This is why the popular name for HSC transplantation is a bone marrow transplantation). This method is still used in clinics. However, it is now more common to use isolated HSCs (called ‘mobilised blood HSCs’). This is possible due to the development of drugs which cause the HSCs to migrate from the bone marrow into the bloodstream. The HSCs can then be isolated from the blood. Bone marrow transplantation and HSC transplantation are used to treat conditions such as leukaemia, lymphoma, and multiple myeloma.  

HSCs can be also isolated from umbilical cord blood (usually just referred to as ‘cord blood’). However, the number of HSCs in cord blood is quite low. Therefore, cord blood is rarely used as a source of HSCs. The majority of cord blood HSC transplants are from non-related donors, and almost none are autologous. Some private companies offer to store cord blood from newborns, for use in treating medical conditions which may arise when they are older. The scientific community has not reached a consensus as to the validity of this approach.  

Current research

Studying the origins of leukaemia

Leukaemias and lymphomas are malignant cancers caused by uncontrolled growth of blood-forming cells. Some types of leukaemias and lymphomas are relatively easy to treat. However, others still give very poor prognosis.  

Scientists are studying how leukaemias and lymphomas develop, to identify targets for new therapies. This research often focuses on pre-cancer syndromes, such as myelodysplastic syndrome. In these cases, patients are diagnosed early, and their condition is monitored.  In many cases their disease will progress to leukaemia, and then the chances of the successful treatment are very low. 

If scientists are able to better understand the mechanisms in HSC which lead to  leukaemia development and progression, they can create better treatment strategies. 

Improving the safety of blood stem cell transplantations

One of the major problems in the use of HSC in therapy is the side effects of HSC transplantations. Many research projects and clinical studies are dedicated to finding better ways of isolating HSC and preparing the patient for transplantation. 

For a HSC transplantation to be successful, the patient’s own HSC must be destroyed, to make space for the transplanted HSC. To achieve this, patients are treated with chemotherapy and/or full-body radiation. Those treatments affect not only HSC, but also many other cells and tissues in the body. The patient’s immune system is severely weakened, and they are susceptible to infections. This is why scientists are trying to develop methods of removing HSC from their niche without using chemo- or radiotherapy. One such new methods is using drugs (antibodies), which weaken the interactions between HSC and their niche in the bone marrow, causing them to leave. This approach is currently being tested in clinical trials. 

One of the most serious complications of stem cell transplantation is graft-versus-host disease (GVHD). This is a condition where transplanted immune cells attack the patient’s own tissues. This happens because the donor-derived immune cells recognise patient’s antigens as foreign, or ‘non-self’, and react as though the patient’s cells are an infection to fight. To make HSC transplantations safer, doctors need to be able to minimize the risk of GVHD.  

When considering using HSC transplant to treat cancers, scientists are trying to establish a proper balance between avoiding GVHD and achieving anti-tumour effect of the transplanted cells. In other words, they are trying to find a way to stop the transplanted cells from attacking healthy tissues, but at the same time not to prevent the transplanted cells from fighting the cancer cells.  

In vitro production of red blood cells

Red blood cells carry oxygen around the body. Patients who lose a lot of blood need to have it replaced straight away by a blood transfusion. There are not enough blood donors to meet patient needs, so researchers are looking for an alternative solution. 

Since pluripotent stem cells have the potential to make any cell type of the body, they could potentially provide an unlimited supply of red blood cells. It is already possible to make small numbers of red blood cells from pluripotent stem cells in the lab, and the first clinical trial of lab grown erythrocytes transfusions began in Autumn 2022. The next challenge is to develop techniques for producing the large numbers of red blood cells that are needed for transfusion.  

 

Next steps

Improving the safety of blood stem cell transplantations

HSC transplantations are standard treatment for certain blood disorders, such as leukaemia or lymphoma. Clinical trials of HSC transplantations for other diseases are ongoing. There are potentially many diseases which could be treated by HSC transplantation, including AIDS and autoimmune diseases, such as diabetes. However, the risk of side effects associated with transplantation are still high enough to prevent use of HSC transplantations for patients who have other treatment options.  

To use HSC transplantations more widely, scientists need to establish safer methods of preparing the patient for the stem cell transplantation and better methods of isolation of pure HSC, without donor’s immune cells. In the future, it may be possible to generate HSC from patient’s own cells (for example using iPS cells).

Growing blood stem cells in the lab 

Finding a proper donor of HSC is sometimes challenging, so scientists are searching for ways to grow a limitless supply of blood stem cells. One possibility might be to collect stem cells from the bone marrow, then grow and multiply them in the lab. Researchers are also trying to make blood stem cells from embryonic stem cells or induced pluripotent stem (iPS) cells. iPS cells could be made from a patient’s own skin and then used to produce blood stem cells. This would overcome the problem of immune rejection. 

 

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