Stem Cell Transplant

1. Introduction:
– Stem Cell Transplant:
All blood cells in the body start as immature, young, cells “Hematopoietic stem cells, meaning blood-forming cells. Most stem cells live in the bone marrow, and then they divide to form new blood cells and stay in the bone marrow until they are mature. Once they are mature, they leave the bone marrow into the blood stream (Craddock, 2009).
Stem cell transplant is used to restore stem cells and blood production when bone marrow is destroyed by a disease, chemotherapy, or radiation therapy. The sources of hematopoietic stem cell transplants vary and can be taken from 3 different sources in the body: The bone marrow of large bones, e.g. Pelvis; Peripheral Blood, Most commonly used; and from Umbilical Cord Blood. All of which are categorized under the Hematopoietic Stem Cell Transplant (Heredia, 2014).
Hematopoietic stem cell transplants are also used prior to initiating cancer therapy for some patients, as the cells are able to transform into any cell type, and further ensure that patients’ bodies are capable of producing enough cells (Craddock, 2009).

– History of Stem Cell transplants:
The Idea: The first bone marrow transplant was delivered orally to patients. They had to eat healthy bone marrow in hopes to find its way into the cell producing cavities. Doctors had the right idea, but the method of treatment was not particularly successful (Pablo, 2015). Eventually, laboratory experiments on mice demonstrated that injured mice with damaged bone marrow were able to become healthy after they were injected with healthy bone marrow from healthy mice. Physicians then started speculating whether such procedure would work on humans successfully (Pablo, 2015).
In 1956, Dr. E. Donnall Thomas performed the first human bone marrow transplant between two identical twins in New York. Thomas stated that bone marrow infusion from identical twins after total body irradiation could result in complete leukemia remission (Liras, 2010).
Jean Dansset, a French medical researcher, then made a breakthrough regarding the human immune system in 1958. He described it as “Human Histocompatibility Antigens”, which are proteins of the most cell surfaces. The immune system uses these proteins to decide which cells belong to the body and which do not. The better the antigen match between the donor and the recipient, the more fitting the bone marrow would be, shifting the main focus of preparing such transplants to the HLA-Antigen match in order to result in a successful transplant (Liras, 2010)).
Dr. Robert A. Good has done the first successful bone marrow transplant between siblings in 1968. The transplant was performed on a 4-month-old baby who had inherited severe combined immunodeficiency syndrome, or Bubble boy syndrome. The donor was the patients’ 8-year-old sister who had a good HLA-matching (Pablo, 2015).
In 1973, a medical team at Memorial-Sloan Kettering Cancer Center in New York carried out the first successful unrelated bone marrow transplant. The transplant was performed on a 5-year-old patient suffering from Combined Immunodeficiency syndrome. The matching donor was found in Denmark through the Blood Bank at Rigshospitulet In Copenhagen. Multiple infusions of bone marrow was delivered to the patient, and after the seventh infusion, engraftment and hematologic normal functions were achieved (Figuerres, 2000).
In 1986, the American Congress approved the formation of the proposed “National Bone Marrow Donor Registry (NBMDR)”, registering 39 donors by the end of that year. From that point in time, medical and cancer centers worldwide started performing bone marrow transplants (Pablo, 2015).
By 1999, scientists have identified new sources of blood-forming cells that can be used in transplantation; these were the introduction of peripheral blood, and umbilical cord blood stem cell transplantations. The discovery of the other sources led to the treatment of many life-threatening diseases that were impossible to cure in the medical therapy field (Pablo, 2015).
2. Objective:
To evaluate the publics’ perception about the applications of hematopoietic stem cell therapy.

3. Literature Review:
3.1. Obtaining Stem Cells:
Stem cells can be obtained from different body tissues or organs, and whether the stem cells collected come from the patients own body or a donor (Gorin, 2000).
An Autologous Transplants:
In this case, stem cells come from the own body of the patient before being infected with a disease. They can also be collected once a patient is fully treated from a disease, if suspecting recurrence of a disease. Autologous stem cell transplants are also called “Stem Cell Support” as the stem cells taken are from the own body of the patient and not literally transplanted from a donor (Figuerres, 2000).
An Allogeneic Transplants:
Allogeneic transplants involve collecting stem cells from a donor, usually a sibling or a close relative, with good HLA-matching. In some cases, allogeneic stem cells transplants can succeed between unrelated donor and patient, as long as there is a good HLA-matching (Hough, 2009).
Allogeneic stem cells come from three different sources of the body: Bone Marrow; The Blood Stream (Peripheral blood); and Umbilical Cord Blood (from new born), says Pidala, 2009.
1-) Bone Marrow Stem Cells:
Bone marrow is the spongy tissue in the center of large bones; its function is to make blood cells that circulate in the body system. They also form into immune cells that fight foreign cells that are recognized by the body as invaders or infections. Bone marrow is very rich of stem cells especially in the pelvic region, which contains most marrow with large stem cell numbers. It is the most common, but not most convenient, source of stem cell transplantation (Hough, 2009).
The Donor of such stem cells must be put into general anesthesia as a large needle is put into the hip until it reached the marrow of the pelvic bone. Then the thick liquid marrow is pulled in the syringe, this process is repeated until enough marrow is collected. The arrow is then filtered and frozen until it is needed for use (Hough, 2009).
When a patient is set for the transplant, the marrow is melted and softened and given into the vein, just like in the process of blood transfusion. The stem cells then find their way to the recipients’ bone marrow and begin to divide over time. The new blood cells formed can be assessed by blood tests in about 2-4 weeks of the transplant (Figuerres, 2000).
2-) Peripheral Blood Stem Cells:
When collecting stem cells from the blood, the donor is given hormone-like substance called “growth factors” before harvesting stem cells from their blood system. Growth factors cause stem cells to travel from bone marrow into the blood stream and cause them also to grow faster (Akkök, 2011).
When harvesting, a catheter is connected to the donors’ large vein and is connected to a tube that carries blood into a special machine. The machine separates stem cells from other blood components and the rest of the components are guided back to the donor’s body after stem cells are collected. This process lasts for 4-6 hours and may be repeated for a few days until enough stem cells are collected (Akkök, 2011).
After the patient has undergone chemotherapy or radiotherapy, stem cells are infused into a vein, in the same way illustrated above in the bone marrow stem cell transplant, and the new cells can be measured a few days sooner than that of bone marrow transplant, usually within 10-20 days (Figuerres, 2000).

3-) Umbilical Cord Blood Stem Cells:
It is the suitable source for patients who cannot find a matched donor among their family members or donors from blood banks, due to its high differential capability and ability to adjust themselves into any immune system. Umbilical cord blood transplants account for about One Third of hematopoietic stem cells transplants. New born babies possess large numbers of stem cells as the blood left in the placenta and umbilical cord can be stored for future use in stem cell transplants. It is usually collected from the blood that is thrown out after a baby is born. The first umbilical cord blood stem cell transplant was done in 1988 and has been increasing ever since. Although only a small number of stem cells can be found using such a procedure, umbilical cord blood stem cells are able to make more cells than that from adult bone marrow (Harris, 2013).
4-) Oogonial Stem Cells (OSC):
Oogonial stem cells are collected from the ovaries of reproductive-age females, which have the potential of giving birth to new fertility treatment and longing the reproductive life (Powell, 2012).
A team of scientists began by developing a method of labeling and collecting mice ovarian stem cells. They used Fluorescent-activated Cell Sorting (FACS) as a technique to attach antibodies to a protein, Ddx4, which resides on the outer surface of stem cells (Johnson, 2004). This method of labeling has the ability to not include dead or damaged stem cells (White, 2012).
The team then labeled the cells with green-glowing fluorescent protein to trace the cells and injected the stem cells into fragments of adult human ovarian tissue that was transplanted under the skin of mice. Within one to two weeks after injecting the cells, the team was able to point additional green-glowing cells that were identified as oocytes and that also expressed two of the genetic hallmarks of this cell type (Zou, 2009) and (White, 2009).
This breakthrough would allow scientists to examine hormones or drugs that might revive these cells to produce eggs in the body, which in turn would lead to slowing women’s biological clock and longing the life or their reproductive system (Powell, 2012).
3.2. The Most Suitable Source of Stem Cells:
As the goal is to transplant healthy stem cells to the patients, the 3 different sources and mechanisms of acquiring stem cells do not have much difference between them. When stem cell transplantation was initially used, all originated from bone marrow. However, the most commonly used currently is peripheral blood stem cell transplantation. Harvesting more stem cells of peripheral blood is a controllable process in which doctors can manage. It is also easier for the doctors to acquire peripheral blood stem cells than bone marrow stem cells even though the process might be more time consuming. The recipients’ blood count, nonetheless, can be measure within shorter periods of time than that of bone marrow stem cell transplants (Gorin, 2000).
The only disadvantage is that the risk of developing chronic graft-versus-host disease is higher in peripheral blood stem cell transplant that in bone marrow stem cell transplants (Pidala, 2009).
When a good match is hard to find for bone marrow or peripheral blood cell transplants, umbilical cord blood transplants is believed to be the suitable option. Although it is best if cord blood is well matched, it does not need to be closely matched as in the extent of bone marrow and peripheral blood cases as suggested by studies (Pidala, 2009). As for patients with rare tissue type, cord blood is considered an advantage. Moreover, blood cord transplants reduce the severity of chronic graft-versus-host disease, but they take longer to engraft causing high-risk of infections to the patient (Gorin, 2000).

3.3. Therapy of Leukimia and Lymphomas:
According to Grosicki 2015, Leukemia is cancer that occurs in cells that are usually developed into different types of blood cell. However, the type of leukemia differs and can be categorized into 4 different types as follows:
-Mature Vs. Immature White Blood Cells:
1-) Acute Leukemia: In acute leukemia, the cancer cells are in the immature phase of blood cells (blasts). This type of leukemia is growing fast as would normal blast cells do. The significance, in this context, is that leukemia cells would not stop dividing and grow faster than normal blast cells, but continue their division and fast multiplication without stopping. Most patients with acute leukemia would live for a few months if no treatment were started. Different types of acute leukemia respond differently to treatment, some would be treated and others are less likely to be cured (Lekakis, 2009).
2-) Chronic Leukemia: They are cancer cells that affect that mature cells of blood components, but they do not act normally. For example, they are unable to fight viruses, infections and other body invaders, as normal white blood cells would do. In fact, they do not fight such invaders at all. Instead, they survive longer than normal blood cells do; they divide and build in the blood stream, and swarm out normal cells. It is true that chronic leukemia progresses over longer periods of time than in acute leukemia, and patients can adapt to living with tem for many years, they are much tougher than acute leukemia to cure (Grosicki, 2015).
-Type of Bone Marrow Cells Affected:
1-) Myeloid Leukemia: they start in myeloid cells that are immature. For example, in white blood cells, platelet-making cells, or red blood cells.
2-) Lymphocytic Leukemia: They affect the immature form of lymphocytes. They differ from lymphomas in that lymphocytic leukemia develops from cells of bone marrow, whereas lymphomas develop in cells of the lymph nodes (Grosicki, 2015).

3.3.2. Lymphomas:
Lymphoma is a type of cancer that affects the lymphocyte making them to behave in an abnormal manner. Such abnormality includes that vast division of cells and the longer proliferation of cells. Lymphomas can develop in many parts of the body including lymph nodes, blood, spleen, or other organs (Angelopoulou, 2014).
There are 2 types of lymphoma; these are Hodgkin lymphomas and non-Hodgkin lymphomas.
1-) Hodgkin Lymphoma (HL):
These are types of lymphomas that involve the Reed-Sternberg Cells in its developmental process. It is neoplastic proliferation of lymphoid cells, the malignancies in this type is in the Reed-Sternberg cells. In most cases, the Reed-Sternberg cells are B-cells and Clonal. They are very large with abundant pale cytoplasm and 2 or more oval lobulated nuclei containing large nucleoli (Ritchie, 2008).
Thomas Hodgkin first assessed HL in 1832, and then Carl Sternberg and Dorothy Reed described the characteristics of Reed-Sternberg cells in 1898 (Adelstein, 2014).
2-) Non-Hodgkin Lymphoma:
They are cancers of the immune system and can occur almost anywhere in the body, but mostly 80% develops in lymph nodes. Its pathology is dependent on 3 aspects; the cell lineage, the degree of cell differentiation, and the location of the cell of origin. This type of lymphoma can simple start any and travel everywhere (Ritchie, 2008).

3.4. Pros and Cons of Stem Cell Transplantation:
The controversy of stem cell therapy is mainly dependent on whether its advantages outweigh the disadvantages, its plasticity and degree of differentiation, availability are also of great deal to carrying out stem cell transplantations.
One of the advantages of adult stem cells is that they can be found in a number of tissues and organs in the body, and can be acquired using a variety of techniques depending of which type of stem cells are needed to be collected. Their high differentiation potential to regenerate the tissue or organ that they will reside in and cure is beyond the required threshold for the success of the procedure. For bone marrow stem cell transplantation, the long-term experience of performing the procedure and the familiarity with the method of acquiring, collecting and administering the stem cells makes the success of such procedure foreseeable as it is being performed for more than 3 decades up until now (Habib, 2006).
In addition, adult stem cells have the ease of identifying homogeneous stem cells and the ease tissue type availability. It is widely availably in such a way that it does not need tissue culture because the number of required stem cells is sufficiently certainly obtainable. Adult stem cells can also proliferate and migrate to the site of injury fast then inhabit and start regenerating the tissue or organ, and within days the progression and new cell count can be measured (Elad, 2014).
On the other hand, the collection of the required number of stem cells in peripheral blood and cord blood stem cell transplantations is somehow difficult. The procedures of collecting peripheral blood stem cells is generally more convenient for both donor and doctors as it can be done in an outpatient settings and does not involve general anesthesia; however, the number of stem cells collected will, in most cases, be lower than that obtained from bone marrow and therefore the procedure might multiple donations to be done over a number of days until enough stem cells are collected for a single patient (Habib, 2006).
Moreover, the number of hematopoietic stem cells is, to a large extent, difficult to amplify because they tend to divide asymmetrically and may in turn result in increased risk of developing genetic instability. Another downfall includes the early complications that are likely to be experienced by the stem cell recipient such as nausea and vomiting, and may lead to further complications as in cases mucositis and interstitial pneumonitis. They can also result in bacterial infections and the development of graft-versus-host disease (Habib, 2006).

3.5. Donor Matching:
Autologous stem cell transplants do not require any type of matching tests because the stem cells collected are originated from the patients’ own body before being diseased (Ji, 2003).
However, in the case of allogeneic transplants, and as the stem cells to be transplanted come from a donor, tissue type match between the donor and recipient has to be close. Otherwise, the recipient’s immune system will recognize the stem cells transplanted as foreign bodies and destroy them, this process is called “ Graft rejection”, and this is a rare case when the donor and recipients are well matched. Another issue that may arise when stem cells are transplanted is when the donors stem cells make their own immune cells, the new cells transplanted may recognize the recipients’ cells as foreign and turn against their new home, this is known as “graft-versus-host disease”. This is the most important reason to find the closest match possible before transplants take place (Hough, 2009).

HLA Matching:
The ability of the immune system to know the difference between which cells belong to the body and which do not is based on many factors, and the most important factor is the Human Leukocyte Antigen (HLA) system. HLA are proteins found on the surface of most cells, they make up the tissue type for a person, which is different from a persons blood type. Each person has a number of pairs of HLA antigens; these antigens are passed from parents to their children, taking a single HLA antigen from each parent resulting in pairs of HLA for each child (Ji, 2003).
Back to stem cell transplantation, the HLA match between the donor and recipient plays a very important role in the success of the transplant, if fact, HLA matching is the key factor to guarantee the completion and achievement of successful transplants. HLA has six major antigens, and the matching tests for all the six antigens to determine how close that match will be. The perfect match is when all the six HLA antigens are matched between the donor and the recipient. Stem cell transplantations with perfects matches have much lower chances of complications such as graft rejection, graft-versus-host disease, developing a weak immune system and serious infections (Couri, 2012).

3.6. After Treatment, and Vaccines:
3.6.1. Engraftment and Preventing Infections:
During the first 2-3 weeks after transplantation, the re-infused cells migrate to the bone marrow and start diving and producing new blood cells. This process is called “engraftment” and it is said to be successful once the body has accepted the new stem cells and started manufacturing new blood cells (Figuerres, 2000).
From the time of infusing and until the time of engraftment, the patient is very vulnerable to developing infections. Due to the high-dose chemotherapy the patients’ immune system is very weakened in a way that a minor cold or flu could be transmitted to the patients causing them serious infection problems (Figuerres, 2000). Patients are usually instructed to follow a certain procedure after transplantation to curb any chance of being infected. These instructions may include: prescription of antibiotics, banning fresh fruits, vegetables and flowers from their surroundings as they may be carriers to bacteria or fungi, and visitors should be wearing gloves, gowns and masks for the protection of patients (Ovayolu, 2013).

3.6.2. Vaccination:
Vaccinations for Streptococcus pneumonia and Haemophilus influenza are recommended for all stem cell transplants recipients. Inactivated vaccine injections should be used for family members who need vaccination against polio, and isolation is necessary if oral polio vaccine is administered to any member who has close contact with the patient during the first year after transplant (Lodi, 2011).
Live vaccines, such as live attenuated influenza vaccine, smallpox vaccine and any other vaccine containing live vaccinia virus, is contraindicated is hematopoietic stem cell transplantation recipients because it may result in the development of generalized vaccinia or inadvertent inoculations at other site such as the face, eyelid, nose, mouth, genitals, and rectum (Lodi, 2011).
For certain high risk groups undergoing high-dose chemotherapy, Anthrax vaccine is highly recommended as it has no dead or live bacteria, it is an inactivated cell-free filtrate vaccine (Elad, 2014).

3.7. Mechanisms of Mobilization:
The term “Mobilization” is defined as the process of which hematopoietic and progenitor cells are employed to the blood following chemotherapy. This process acts the same way as the physiological release of stem cells from their reservoir in response to stress signals during injury or inflammation (Angelopoulou, 2014). Currently, the mobilization of hematopoietic and progenitor cells is the most commonly used method is stem cell transplantation because the stem cells are usually harvested from either peripheral of cord blood resulting in higher yield, faster engraftment, and decreased procedural risk. Stem cell mobilization involves the introduction of physiological interplay between mesenchymal stromal and hematopoietic cells regulating both bone and bone marrow remodeling process, which in turn mediates stem cell division, proliferation and migration (Angelopoulou, 2014).
The process of mobilization is initiated by the activation of neutrophils and osteoclasts by stress induced activation when receiving chemotherapy. Increased cell release from the bone marrow reservoir is part of the immune system host defense during inflammation that is caused by injury or infection (Angelopoulou, 2014).
There is a number of methods for the mobilization of stem cells, each methods has its own factors that affect the way stem cells are mobilized, the yield they result in, and the side effects they might cause the patients to have (Angelopoulou, 2014).
According to Angelopoulou in 2014, the most commonly used method of mobilizing stem cells is by using Granulocyte Colony-Stimulated Factor (G-CSF) as a standard physiological agent and sometimes in combination with other agents. For patients with Non-Hodgkin Lymphoma, it is recommended to use steady-state mobilization with G-CSF alone due to its low toxicity, although its failure rate might be higher in some cases. Chemo-Mobilization, or CM, is also appropriate method of mobilization whether it is incorporated into the initial 3-6 cycles of chemotherapy or as a part of a salvage regimen.
However, the debate on whether the best approach is to mobilize stem cells with Growth Factors, G-CSF or CM or a combination of G-CSF and CM method is not over and has yet to be determined (Angelopoulou, 2014).

3.9. Preservation of Umbilical Cord Blood Stem Cells and Its Cost:
After the collection of umbilical cord blood stem cells and until they are needed for a transplant, the plasma, and sometimes RBCs, is removed from cord blood and then the stem cells are stored at very low temperatures of liquid nitrogen vapor phase. Although the lifetime of stem cells while being stored has not been fully determined, scientists believe that it would definitely be more than 20 years of storing as more than 99% of stored stem cells that have not been used within 20 years remained viable (Zimmerman, 2015). Most transplant experts suggest that umbilical cord blood stem cells may remain viable indefinitely. The cost of storing stem cells is approximately $150 U.S.D. paid on annual basis along the period of storing (Stemcyte, 2016).

3.9. Clinical Applications of Stem Cell Transplantation:
In the last two decades, the interest of stem cell research has increased dramatically not only for the medical and scientific community, but also among religious groups, politicians and ethnicities. Human stem cells are being utilized in a number of therapeutic procedures and, as they have the ability to transform to many cell types, they are being studied on large scales to treat different types of cancers, infections and chronic diseases (Habib, 2006).
Stem cell transplantation has shown outstanding improvements in curing many diseases such as the treatment of cardiovascular diseases, multiple sclerosis (MS), leukemia, and lymphoma (Harris, 2013).

3.8.1. Cardiovascular Repair:
Q. Sun in 2014 stated that the addition of myeloid derivatives as donor cells to hematopoietic stem cells might provide more effective cell-based therapy for cardiac repair. The hint here is using hematopoietic stem cells in cardiovascular repair implies that they are likely to achieve the goals required for stem cell transplant. However, their low frequencies, difficult maintenance in cell culture, and the unknown signaling pathways that control the proliferation and differentiation of stem cells should be further studied. Nevertheless, specific induction of hematopoietic stem cells into cardiomyocytes must be generated to avoid tumor genesis.
3.8.2.Multiple Sclerosis (MS):
Stem cell transplantation could help in treating MS by two processes; Immunomodulation or Remyelination. Immunomidulation method works by preventing immune damage to the nervous system, to maintain its fully functionality and stop damaging the myelin sheath that causes the relapses of MS in first place (Tesar, 2015).
The Remyelination process takes place in a way that stem cells are capable of repairing the myelin sheath that has already been damaged by promoting the nervous systems’ own mechanisms of repair to deal and repair the damaged sheath (Tesar, 2015).

3.8.3. Leukemia:
Studies have shown that allogeneic transplantations have the ability to cure patients with leukemia but the risks are significant due to the high toxicity when cellular immune therapy is used in combination with chemotherapy (Lekakis, 2008).
3.8.4. Lymphoma:
Stem cell transplants aim to improve the quality of life of patients, prolong remission and eventually cure lymphoma. Stem cell transplantation can be used for patients who have already undergone earlier courses of treatment, for those who failed to respond to treatment, or to prolong remission for patients who are likely to be at higher risk of relapse (Ritchie, 2008).
Most lymphoma patients treated with stem cell transplants are those with Hodgkin lymphoma or higher-grade non-Hodgkin lymphoma who have relapsed after the first course of treatment. The goal of such procedures in this context is to provide prolonged remission as a start, and then cure the lymphoma if possible (Angelopoulou, 2014).

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