Maariya Rachid Daud

 

Glossary

Amino Acid, Anemia, Arteries, Biobanks, Blood, Bone marrow, Cancer, Carcinogenesis, Carbon Dioxide, Cardiovascular, Conditioning Regimen, Cord bloodEmbryo, Endothelial Cell, Epithelial Cells, Fetus, Glucose, Graft Versus Tumor, Graft Versus Host Disease, Hematopoietic Stem Cells, Homeostasis, Immunophenotyping, Leukemia, Lumen, Mesenchymal, Metabolic disorders, Oxygen, Peripheral blood, Pregnancy, Receptors, Red blood cells, Sickle Cell Disease, Stem Cells, Stem Cell Transplantation, Total Body Irradiation, Umbilical Cord Blood, Uterus, Vein

Abbreviations

UCB, Umbilical cord blood; SC, stem cells; HSC, hematopoietic stem cells; MSC, Mesenchymal stem cells; VSELs, Very Small Embryonic-Like stem cells; CMP, common myeloid progenitor; MEP, Megakaryocyte-erythroid progenitor; GMP, Granulocyte-macrophage progenitor; ESCs, Epithelial Stem Cells; TBI, Total Body Irradiation

Introduction

During pregnancy, the umbilical cord is one of the essential structures used to connect the mother to her child allowing the exchange of all the essential nutrients, including oxygen, contributing to the baby’s survival. The umbilical cord is a flexible tube that is developed from an organ known as the placenta during the first trimester of pregnancy. After the baby is born, the placenta and umbilical cord both detach naturally from the mother’s uterine wall. In the past, the umbilical cord was viewed as biological waste and discarded appropriately. However, in the late 1900s, researchers found that the blood in the umbilical cord, known as umbilical cord blood (UCB) contained special cells called stem cells that could be used to treat several diseases. The stem cells in UCB can differentiate and become other important cells contributing to the treatment of diseases including certain cancers and immune, metabolic disorders, and blood disorders (1).

Umbilical Cord

The umbilical cord begins to develop, at roughly the same time, as the development of all the other organs, usually in the first trimester of pregnancy, also referred to as the early stages of embryonic development. During this time, the umbilical cord begins to form a flexible tube as illustrated in Figure 1. In the second trimester of pregnancy, the umbilical cord starts to elongate to an average length of 50-60 cm with a diameter of two cm. The umbilical cord plays a crucial role in the survival of the fetus providing it with essential nutrients. Any abnormalities in the umbilical cord can easily impact the overall health and survival of the baby (2). To ensure that there are no major abnormalities, a sonographic analysis of the umbilical cord is normally taken during pregnancy (3).

Figure 1 Composition and anatomy of the human umbilical cord.

The umbilical cord is comprised of a cord lining surrounding the umbilical cord, the Wharton’s Jelly, cord blood found in the umbilical vein, a perivascular region, and an endothelium. Different types of stem cells can be found in the different parts of the umbilical cord (4). Figure made in Biorender.

The umbilical cord is a long tube comprised of three blood vessels as demonstrated in Figure 1. Two arteries and one umbilical vein surrounded by the connective tissue known as the Wharton’s Jelly make up the umbilical cord (4). Arteries and veins are found all over our bodies, not just in the umbilical cord, and are two of the most important components of the cardiovascular system used to transport oxygen, hormones, and nutrients to different parts of the body (2). Arteries are used to carry the oxygenated blood away from the heart contrasting to veins that carry the deoxygenated blood towards the heart. Veins have a thin wall, large lumen and valves that allow them to keep the blood flowing towards the heart, contrasting to the small arteries that carry oxygen towards a variety of cells away from the heart (3).  In the case of the umbilical cord, the umbilical vein supplies oxygen, glucose, and amino acids to the fetus, and contains umbilical cord blood, whilst the two arteries in the umbilical cord help with the removal of waste products including carbon dioxide excreted from the fetus (2). The Wharton’s Jelly plays an important role in providing protection and structural support (2). After the baby is born, the umbilical arteries begin to close due to the contractions generated by the vascular wall. The umbilical vein only closes after the umbilical arteries have been closed, providing sufficient time for the removal of cord blood from the umbilical vein (3). The variety of stem cells are found in the UCB which is easy to collect, store and use when necessary.

Nevertheless, the different parts of the umbilical cord are also comprised of a variety of stem cells. These are shown in Figure 1. These cells can also be easily extracted without harming the mother or the baby. There have been many studies highlighting and proving that umbilical cord stem cells can be frozen over long periods of time and still possess their regenerative properties a decade later (4).

Umbilical Cord Blood (UCB)

Our blood also referred to as the peripheral blood, is composed of a variety of components that facilitate the transportation of oxygen, nutrients and hormones and also discards waste products like carbon dioxide. The different components in the blood like plasma, red blood cells, white blood cells and platelets help the blood conduct its functions. Similarly, umbilical cord blood (UCB) contains the same components, with the main difference being that the amount of stem cells in the cord blood is much higher compared to peripheral blood (5).

In the past, the umbilical cord and its blood were considered to be biological waste. However, in 1988, umbilical stem cells were successfully derived and used in the clinic on a 6-year-old boy who suffered from anemia. Shortly after, the first private cord blood bank in the world (5) called Cryo-Cell was established in 1989 and is still internationally recognized as a well-established cord blood bank (6). Even though UCB isn’t the only place where stem cells can be extracted, the quality of stem cells is better compared to the stem cells found in other places including bone marrow and peripheral blood. The amount of stem cells from UCB required for transplantation is 10 times less compared to the number of stem cells found in peripheral blood and bone marrow. In addition, the number of HSCs in 80 to 120ml in UCB is equivalent to the number of HSCs in 1200ml of bone marrow. This reinforces the need for the SC derived from UCB (5).

Stem Cells in Umbilical Cord Blood

Many types of cells make up the human body including red blood cells, muscle cells, and epithelial cells. All these cells are defined as differentiated cells as they already have a specific role and function in the body. Alternatively, stem cells can be classified as undifferentiated or unspecialized cells as they can divide to develop into different cell types depending on the type of stem cell. For a cell to be classified as a stem cell, it needs to be able to either self-renew or differentiate during cell division. Cell division is a process which occurs in all cells, both specialized and unspecialized, and is where the cell splits into two daughter cells. Self-renewal refers to a stem cell that produces another stem cell during cell division. On the other hand, differentiation is the term used for cells which have differentiated into specialized cells. The process of differentiation also occurs during cell division (7). More information about stem cells can be found in another Personalize My Medicine article written by Lovisa Lindquist.

Figure 2 Differentiation of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) derived from umbilical cord blood. HSCs differentiate into common myeloid progenitor (CMP) cells that later further differentiate into two other different cell times that further differentiate into numerous cells. This contrasts with MSCs, which differentiate into 5 different types of cells initially. Made in BioRender.

Umbilical cord blood (UCB) is comprised of a variety of different types of stem cells all of which can differentiate into various cells possessing a wide range of properties that could aid in the treatment of numerous diseases. The main types that have been studied the most intensively are Hematopoietic stem cells (HSCs) and Mesenchymal stem cells (MSCs). These types of stem cell have unique properties in the way that they to differentiate into different types of cells that can be used in the treatment of various diseases. HSCs can differentiate into a variety of blood cells to treat blood-associated diseases such as leukemia and anemia. MSCs differentiate into a variety of tissue types and can be used during tissue regeneration (8).

Hematopoietic stem cells (HSCs)

HSC are a type of immature cells that self-renew and can differentiate into all types of blood cells. HSC play an especially vital role throughout the lifetime of organisms as all lineage blood cells can be produced by the multipotent HSC. This includes the production of red blood cells (cells that transport oxygen around the body), platelets (cells that help with the control of bleeding) and white blood cells (cells used for the immune system). Examples of other blood cell types that can be produced from HSC are illustrated in Figure 2. Due to the diverse potential of HSC and their importance, they can be used in the treatment of many blood-related disorders including leukemia and sickle cell disease (9).

Mesenchymal Stem Cells (MSCs)

MSCs are stromal cells with a variety of properties such as self-renewal and multilineage differentiation. Stromal cells are cells that make up the connective tissue which is the tissue supporting tissues and many organs. The majority of the MSCs can be derived from Wharton’s Jelly in abundance, but some can be found in UCB. Some of the cells that can be differentiated from MSCs are illustrated in Figure 2 including adipose, cartilage and bone cells.

MSCs are different from HSCs with the main difference being the cells that they differentiate into. To distinguish between the MSCs from the HSCs, certain markers can be looked into. For example, MSCs lack the markers CD34, CD45, CD14 and HLA-DR from the surface of all their cells (10). All cells have certain molecules on their surface, known as markers allowing for their differentiation in the process known as immunophenotyping. The CD molecules play important roles in the cells as they will act as either receptors or ligands that play a crucial role in cell-to-cell interactions (11).

Epithelial Stem Cells (ESCs)

ESCs as the name suggests can differentiate into epithelial cells and are most commonly found in the umbilical cord lining. These stem cells are crucial as they are responsible for the maintenance of the tissues throughout adulthood and play important roles in tissue homeostasis, wound repair, and carcinogenesis. ESCs exhibit CD44, CD54 and CD104 markers on their outer surface and research has shown that they have the potential to be useful in clinical epidermal reconstitution (12).

Collection and Storage of Cord Blood

Before cord blood can be stored, the mothers need to be tested for any infections such as hepatitis and HIV to ensure that it is not transmitted to the recipient. The cord blood can then be collected by either the obstetrician-gynaecologist or other staff at the hospital post-birth. After the birth of the baby, the umbilical cord is clamped and cut and the blood from the umbilical cord and placenta can be collected into a sterile bag with the use of a needle. Blood is usually drawn from the cord using a needle with the bag attached. The entire process of collecting cord blood is simple and takes approximately ten minutes (13).

Figure 3 Collection and storage of cord blood

The figure shows the process used for collecting and storing cord blood. 1) Umbilical cord is extracted from the baby, 2) Umbilical cord is clamped, and the blood is stored in a blood bad, 3) Clinicians will evaluate the blood for diseases or potential problems, 4) Blood is delivered using a specialized vehicle, 5) Cord blood is ready to be stored at extremely low temperatures using liquid nitrogen in a biobank. Made in BioRender.

After the cord blood has been successfully collected using the process highlighted in Figure 3, it is normally stored in a biobank. There are two types of banks where cord blood can be stored, public banks and private banks. The main difference between the two types of banks is who the cord blood is used for and the cost. Naturally, public banks are more expensive and can charge between $1350 and $2350. The cost of private blood banking normally includes collecting, testing, and registering and most private cord blood banks also charge annual maintenance fees ranging from $100 to $175. This contrasts dramatically with public cord blood banks which store and collect cord blood for free (14).

While the cord blood that is being stored in public cord blood banks can be used for any suitable patient, private cord blood banks store the cord blood for use by only for the family that donated it. There are many advantages to storing cord blood publicly as it ensures that anyone with a medical condition and needs cord blood has access. Many public banks ensure that all cord blood samples are registered in a database so that they can be easily identified and matched with patients worldwide. Private blood banks are more limited in the way that they can only be accessed by the donor family and are sometimes never used. In general, diseases that require cord blood transplantation are exceedingly rare and estimates are suggesting that only around one in 400 to one in 200,000 babies will need their cord blood in the future and probably need to store their cord blood in private blood banks. Due to this, it is highly recommended by the American Academy of Pediatrics (AAP) to store cord blood publicly, if possible, to reduce wastage. It is estimated that the chances of cord blood being used in public cord blood banks are thirty times greater compared to private blood banks. Nevertheless, if there is a high susceptibility to a disease that can be treated with cord blood in the family, private cord blood banking may be the solution. This ensures that cord blood is readily available in cases of emergency and the likelihood of finding a match for someone in the family is much higher compared to public banks (14).

Transplantation of the stem cells

Stem cell transplantation involves the transplantation of healthy stem cells from a donor to a recipient. Before the recipient undergoes transplantation, they will need to undergo conditioning therapy. Conditioning therapy is essential as it prepares the body for the transplantation and acquisition of new cells. This process is normally done using chemotherapy, and depending on the person it may be used in conjunction with total body irradiation (TBI). During this process, the old remaining abnormal cells will be removed preparing the body for the new incoming stem cells (15).

The cord blood will then be prepared for thawing in a water bath and the blood will be transfused into the recipient in a similar way as a blood transfusion.  The transplantation usually happens one day post the finishing of conditioning therapy. During the transfusion, the stem cells from the cord blood will naturally migrate to the bone marrow in a process known as engraftment. Depending on the disorder, the cord blood stem cells will act differently. For example, in the treatment of cancer, the cord blood stem cells will recognize and attach any of the remaining cancer cells in a process known as graft versus a tumor or sometimes referred to as graft versus leukemia (15).

The recovery from cord blood transplantation usually takes around six months to a year. However, the good news is that patients normally only stay in the hospital for around four to six weeks. The hospitalization part of recovery is important as it will protect the patient from acquiring infections. In addition, it is normal for patients to have some side effects post-transplantation. Some of the short-term side effects that can occur include a higher risk of infections, liver and kidney problems, tiredness, diarrhea and loss of appetite.  In some cases, patients may get longer side effects due to the body taking time to uptake the new stem cells. After transplantation, the recipient’s immune system needs to accept the donor stem cells, and if they are not recognized they can cause a condition known as graft versus host disease (GvHD), which is one of the long-term side effects. Other two common long-term side effects include a higher risk of infection and extreme tiredness, known as fatigue, simplified in figure 4 (15).

Figure 4 Transplantation of stem cells

For a successful transplantation, the patients undergo chemotherapy, followed by stem cells being infused into the body and medication to prevent rejection. Nevertheless, when undergoing transplantation, the recipient is still prone to post-transplantation side effects including inflammation, diarrhea, liver problems and fatigue. Made in Biorender.

Graft versus host disease: HLA matching

After the collection and storage of cord blood, the various stem cells can be used to treat different diseases. However, a match between the donor of the cord blood and the recipient is crucial for the transplantation to be a success and reduce the likelihood of an infection occurring. Under normal conditions, it is recommended that stem cell transplants are carried out using stem cells donated by a close family member as this decreases the likelihood of rejection (15).

The outer surface of every cell in our body has specific marker proteins, known as antigens. These antigens are crucial for our immune system as they allow the differentiation between our cells or foreign cells, cells that do not belong to our body. Human leukocyte antigens (HLA) are antigens present in most of the cells in our body. HLA was named after their discovery on the surface of leukocytes, but later was found to be present on the surface of all cells (16).

Every cell in the body has over 200 HLA markers. However, only six HLA markers are assessed for using the DNA of both the donor and recipient after a simple cheek swab. This is because these 6 HLA markers are used by the immune system to target foreign cells. The HLA markers are all coded by the gene on chromosome 6 and are known as HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DP, and HLA-DQ (17). Doctors will evaluate for these markers in the DNA of both the donor and recipient to determine if they are a match and will not cause rejection. The HLA markers are passed down from each parent giving siblings a 25% chance of having the same markers. It is estimated that only 30% of people will be able to find a match within their family meaning that 70% of people need to find their match from other sources like biobanks. Due to HLA markers being inherited from parents, the likelihood of finding a match between someone of the same ethnicity and family is more likely (16).

The immune system will use the HLA on the surface of the cells to distinguish between self-antigens, present on the surface of our body’s cells and non-self-antigens, present on the surface of foreign cells. Normally, when the immune system recognizes non-self-antigens, it will activate an immune response targeting the foreign cells. The body’s immune system will attack the transplanted donor cells causing rejection and graft versus host disease (GvHD) as illustrated in Figure 5 (16).

Figure 5  Graft versus host disease (GvHD)

When the stem cells for the cord blood are transfused into the patient, one of the things that can occur is called GvHD. During GvHD, the immune system views the transplanted cells as foreign and produces an immune response involving B cells, Dendritic cells and CD4+ cells. Cytokines or antibodies will then ‘fight’ the transplanted cells resulting in unwanted side effects. Made in Biorender (16).

There are two types of GvDH which can occur known as Acute and Chronic Graft versus Host disease. Acute GvHD occurs quite early on, in the first three months of the transplant and is estimated to occur in 20-25% and 30-35% of transplants between siblings in children and adults, respectively. After the development of acute GvHD, there is a 50% chance of developing chronic GvHD.  Chronic GvHD normally occurs three to 18 months post-transplantation and affects approximately 30% of people who got their stem cells from HLA-matched siblings (18).

Advantages of Umbilical Cord Blood

Stem cells can be collected from a variety of various places, however obtaining them from the umbilical cord as opposed to bone marrow has proven to be more advantageous for several reasons. One of the main advantages of using umbilical cord blood includes its abundance and availability. Researchers have found that there is a greater availability of stem cells in UCB as opposed to other places like bone marrow (5). However, in general, one of the biggest advantages of umbilical cord stem cells is that they can be extracted without causing harm to the mother or the baby.

In addition, stem cells derived from the umbilical cord are less likely to cause Graft vs Host disease (4). This is because cord blood is made up of a naïve immune system, meaning that the immune cells are less mature and experienced, meaning that they have encountered fewer foreign substances, compared to the immune cells found in adult sources, including the bone marrow. Having a naïve immune system also means that cord blood will have fewer T cells that may react with the tissue of the recipient (19).

Stem cells in modern medicine

Stem cells have unique and distinctive features that allow them to differentiate into various cell types. Stem cells are currently a promising groundbreaking area of research and have big potential to revolutionize modern medicine. Some of the common areas of research and disease that stem cells have been involved with are highlighted in Table 1.

Table 1. Umbilical cord blood has many uses and can treat a variety of disorders. Some of the disorders that can be treated using stem cells derived from the umbilical cord include blood disorders, cancers, immune disorders, metabolic disorders and bone disorders. The table provides some examples of the disorders and their categories.

There has been a substantial amount of work that has been conducted using stem cells derived from the umbilical cord. Many clinical trials are currently undergoing to investigate the use of stem cells in modern medicine. Recently, two papers were published discussing the use of stem cells derived from cord blood for patients suffering from autism spectrum disorder and patients with chronic spinal cord injury. Even though both the studies conducted showed promising results, further research needs to be conducted considering that there were no clear results (20).

In general stem cells, not just umbilical cord-derived stem cells, offer limitless opportunities. Some examples in modern medicine of the use of stem cells involve their use in regenerating and developing restorative medicine due to the cell’s ability to differentiate. This can be proven to be very beneficial to professional sportsmen who suffer from tendon injuries which do not have regenerative properties. Clinical trials have been conducted on trying to treat Osteonecrosis of the femoral hip, a refractory disease. In these clinical trials, it was shown that stem cells were able to reduce pain and improve the function of the hips. In addition, stem cells are also being used in a pharmacological environment as they can be used in new drug tests. By using specific differentiated cells, researchers can investigate the drug of interest and its effectiveness on live tissue before clinical trials and without harming any live testers (21).

Summary

To summarize, the umbilical cord blood derived from the umbilical cord contains a variety of stem cells including HSCs and MSCs which have been studied and proven to be very beneficial in modern medicine. There are many sources of stem cells, however, umbilical cord blood-derived stem cells are one of the easiest methods of obtaining and storing them. The umbilical cord blood can be extracted from the baby in a pain-free fashion, stored in a blood bag in liquid nitrogen in a biobank. Whilst there is a possibility, of some side effects after transplantation including GvHD, there are many advantages. Due to the ability of the stem cells to be able to differentiate into other cells, it is possible to use them for different diseases depending on the condition. Recent papers have shown the successful use of stem cells in treating patients suffering from autism spectrum disorder, chronic spinal cord injury and tendon injuries. Nevertheless, a lot of research still needs to be conducted on stem cells specifically derived from cord blood.

 

References

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