Bone marrow donation: the oldest form of regenerative medicine

Updated: Jun 16

Authored by Lucy Smith and The Durham Bone Marrow Society


Every 20 minutes someone in the UK is told they have blood cancer: according to the charity Bloodwise, it is the 5th most common cancer in the UK. For some patients, a stem cell transplant is their last chance for survival. But what exactly are stem cells? What is the scientific basis of stem cell transplantation? And, most importantly, how can I be a potential stem cell donor?


What are Stem Cells?

Stem cells are defined by two key properties:

· The ability to indefinitely divide and self renew

· The ability to produce new cells which have a highly specialised, specific function


Why is this important? Most cells in the human body do not have the ability to divide and produce new cells, so when new cells are required to replace old cells, these must come from stem cell populations. These unique cells are found at all stages throughout the life, in the embryo and the adult human, but differ in their potency – their ability to create new specialised cells (see Table 1). Generally, only embryonic stem cells are totipotent or pluripotent, whereas adult stem cells are multipotent or unipotent.


Table 1. Potency of stem cell populations


Haematopoetic stem cells

All stem cells have a crucial role in maintaining the organs of the human body. Haematopoetic stem cells (HSCs) have a major role in forming the various cell populations that constitute blood – such as red blood cells and white blood cells – each of which has a specific role, whether that be carrying oxygen or dealing with infection. As HSCs are multipotent, all of these cell types can be produced from the HSC population: the process relies on a series of cell divisions, with each new cell becoming more differentiated and specialised (i.e. less multipotent) – see Figure 1. Defects in this process or a lack of functional HSCs leads to severe problems and impacts on health. While HSCs reside in multiple sites in very young children including bones, spleen and liver, as humans age, HSCs and therefore haematopoesis (the process of forming blood cells) becomes restricted to bone marrow.



Figure 1. Haematopoietic stem cells and its production of blood cells: Each cell division results in the formation of a new cell which is more specialised and less multipotent. Eventually, the highly specialised cells that constitute blood are formed. Abbreviations: HSC: haematopoietic stem cells; LT-HSC: long term haematopoietic stem cells; ST-HSC: short term haematopoietic stem cells; MPP: multipotent progenitor; CLP: common lymphoid progenitor; CMP: common myeloid progenitor; GMP: granulocyte monocyte progenitor; MkEP: Megakaryocyte-Erythroid Progenitor. (Hole, Oct 2017)

Why would someone need a stem cell transplant?


HSCs play a crucial role in the human body, forming the constituents of blood. Issues with HSCs and their derivatives can result in severe impacts on health. Example problems include:


· Defects in HSC function: inability of HSCs to form all components of blood, such as aplastic anaemia.

· Defects in resultant blood cells: dysfunction of HSC derived cells, such as leukaemia or lymphoma.

· Destruction of HSCs due to external source: Examples include exposure to chemotherapy treatment or ionising radiation, leading to destruction of HSC reserve in bone marrow.

In general, all of these issues will lead to a deterioration in health, and symptoms may include an inability to fight infection effectively, difficulties clotting and ineffective oxygen transport resulting in breathlessness and fatigue. Transplantation of HSCs can alleviate these symptoms, due to integration of the new cells into the bone marrow. HSC transplantation may be autologous, from the patient’s own cells, or allogenic, from another person, depending on the HSC defect. Patients with genetic HSC conditions cannot undergo autologous transplantation due to the presence of the same dysfunctional DNA in every cell in the patient. Thus the generosity of strangers willing to undergo allogenic transplantation is their only option.

What is the HSC transplantation process?

There are three steps to the allogenic HSC transplantation process.


1) Bone Marrow Ablation

Before transplantation, the patient's own haematopoietic system (bone marrow) must be destroyed to allow the newly transplanted cells to populate the bone marrow. Chemotherapy is the most common method of ablation, whereby any of a wide range of drugs are used to reduce the number of dysfunctional HSCs in the patient. Once dysfunctional cells are undetectable, HSC transplantation can occur.

2) HSC harvesting

There are two main sources from which HSCs can be harvested.

· Bone marrow: HSCs are harvested from the iliac crest of the pelvis by aspiration via a needle. This is possible due to the thin bine covering, lack of protective muscle and large volume of marrow.


· Peripheral blood: A small number of HSCs can be found in blood due to migration, but treating donors with G-CSF (granulocyte colony stimulating factor, usually produced during infection) just before harvesting can result in a 50 fold increase in HSCs in peripheral blood. To harvest, blood is extracted through a needle, run through a blood pheresis machine to extract HSCs and returned to the patient.


3) HSC transplantation

For autologous transplantations, the patient's own HSCs are harvested, frozen, and transplanted back into the patient via reinfusion. For allogeneic transplantations, a donor's HSCs are harvested and transplanted back to the patient via infusion into a blood vessel. Following transplantation, patients undergo life long monitoring in order to ensure health, monitor rejection and detect potential relapse in cases of cancer.

HSC transplantation is unique, as a single cell type is sufficient to reconstitute the entire haematopoietic system, which is not the case is many other organs. Additionally, HSCs have the ability to return to bone marrow independently; many regenerative therapies require tissue formation directly in the appropriate anatomical site. Finally, as HSCs self renew, a single transplantation should be sufficient for a lifetime – humans usually have around 7 generations worth of HSCs in their bone marrow. Such characteristics of HSCs make this procedure easier compared to other organ transplants, as donors can donate during their lifetime, and transplantations are less invasive.

The genetics behind HSC transplantations

In order for HSC transplantation to be successful, the recipient and donor must be closely matched for human leukocyte antigens (HLA). In humans, the HLA system is a series of cell-surface proteins found on all cells, involved in the crucial activity of identifying whether cells are ‘self’ or ‘non-self’ (Choo, 2007). Located on chromosome 6, HLA genes are highly polymorphic, which means they are highly variable and there are many different versions (known as alleles). This allows for specificity from person to person, and ease of self-recognition. However, this poses a problem for HSC transplantation, making it very difficult to find an exact match between the patient and a potential donor.


But why is HLA matching between the patient and the potential donor so important? The degree of HLA match is strongly predictive of clinical outcome. The higher the degree of the match, the more likely the transplant is to be successful as the HLA from the patient's cells and HLA from the donor's cells will be similar and so will not recognise each other as foreign (Delves, 2018). When the HLA matching is low, unsuccessful outcomes including transplant rejections and Graft Versus Host Disease (GVHD) can occur (Kanda, 2013). In transplant rejections, the recipient recognises the HSCs as foreign and initiates an immune response to destroy the transplanted HSCs. In GVHD, the transplanted cells recognise the recipient as foreign and begin destroying the recipient’s cells. Both conditions result in widespread tissue damage, can lead to transplantation failure, and in extreme cases cause death.

As HLA type is inherited directly from parents, with half of the genes coming from each, the more “related” the donor and recipient are, the higher chance of a successful stem cell transplant (Choo, 2007), e.g. there is 25% chance of a patient being an identical match a sibling. Also, as some HLA types are less common than others, patients are more likely to match someone with a similar ethnic background or ancestry (Choo, 2007).

How are potential HSC donors found?

Normally, the siblings or family members of a patient are screened to see if they have a minimum of 90% HLA match to the patient (Choo, 2007). For patients who cannot find a match within their family, the stem cell register is the next stop to find a potential donor.

There are two HSC registers in the UK, one of which is the Anthony Nolan Stem Cell Register. Founded by Shirley Nolan in 1974 to find a potential donor for her 3-year-old son Anthony, the charity continues to register potential donors and create donor to recipient matches in the name of Shirley’s son.

The stem cell register has a vast database of potential stem cell donors, usually recruited from donor registration events, where registrants do a cheek swab which is then sent to Anthony Nolan’s labs to type their HLA genes for matching with future patients in need. This method has allowed Anthony Nolan to make over 1000 matches every year through their register, even conducting the search on a global scale.

Ending Remarks

Anthony Nolan performs crucial and inspiring work to save the lives of those with blood cancer and blood disorders. They find donor to recipient matches for patients who are in need of a stem cell transplant and aim to one day provide a donor for every patient in need. On top of this extensive register, Anthony Nolan also conducts ground-breaking research to increase the effectiveness of transplantation, supports patients throughout the process and raises awareness surrounding the realities of living with blood cancer.

The stem cell register is vital in enabling transplantation for patients in need. This is why the work of Anthony Nolan, and all Marrow groups by association, is so vital to those suffering from blood cancers and associated disorders. With every new donor on the register, the survival rate becomes more optimistic. The science behind the work Anthony Nolan does may be extremely technical, and the transplants high-risk, but one day of generosity from a donor can add many days to the lives of those in need.

If you wish to register as a potential stem cell donor, attend the donor registration events that happen throughout the year and are conducted by Marrow Societies. In Durham, the Durham Marrow Society exists and runs donor registration events throughout the year.

References:

Choo S. Y. (2007). The HLA system: genetics, immunology, clinical testing, and clinical implications. Yonsei medical journal, 48(1), 11–23. doi:10.3349/ymj.2007.48.1.11

Kanda, J. (2013). "Effect of HLA mismatch on acute graft-versus-host disease". International Journal of Hematology. 98 (3): 300–308. doi:10.1007/s12185-013-1405-x. PMID 23893313

Delves, Peter J. “Human Leukocyte Antigen (HLA) System - Immunology; Allergic Disorders.” MSD Manual Professional Edition, MSD Manuals, Dec. 2018, www.msdmanuals.com/en-gb/professional/immunology-allergic-disorders/biology-of-the-immune-system/human-leukocyte-antigen-hla-system.

Roosnek, Eddy, and Nicolas Guyot. HLA Genes and Molecules, 2015, medweb4.unige.ch/immunologie/home/HSC/transplantation_barriers/structures_recognized/major_histocompatibility_antigens/genetic.php.

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