the late 1800s the term, stem cell appeared in the scientific literature of the notable biologist Ernst Haeckel, but it wasn’t until the Russian-American scientist Alexander A. Maximow that the theory of hematopoietic cells came forward. The theory stated all blood cells have a single precursor cell, and hence are multipotent with the ability to further differentiate.
Blood cells, one of the most relentless cells of the adult human body, have an enormous regenerative capacity. They originate from hematopoietic stem cells. These were first discovered in experiments where mice were lethally irradiated and these stem cells regenerated the hematopoietic system. From these experiments, human trials showed that such stem cells exist in the body and are responsible for the continuous replenishment of adult blood cells.
Types and Markers
There are two types of hematopoietic stem cells (HSCs): long term and short term. As the names suggest, long-term HSCs proliferate for a lifetime while short-term HSCs only last for a period of up to four months and are usually committed progenitors. It is difficult to differentiate between these two types because no set markers have been identified for them; however, Irving Weissman did propose a set of markers in humans, which were similar to those found in mice HSCs.
Glycoproteins CD34+ and CD133+ identify human hematopoietic progenitor cells. Most human marrow or blood CD34+ or CD133+ cells are committed progenitors, and only a small minority are long-term stem cells.
Functions
Regenerative potential
One of the basic functions of hematopoietic stem cells is self-renewal, the reason for the multiple applications in the treatment of diseases. Over the course of years, scientists have endeavored to culture human hematopoietic stem cells but it has proven difficult as cultured HSCs rush to differentiate, although many studies have been conducted on animal cells. Telomerase is an enzyme that expands the regions of DNA called telomeres (present at the ends of the chromosomes), and long-term stem cells have been linked to increased telomerase activity and thus the properties of self-renewal.
Figure 1 Haematopoietic stem cell differentiation
Differentiation
Another function of HSCs is differentiation. Hematopoietic stem cells give rise to myeloid and lymphoid precursor cells, which then further differentiate to adult blood cells (i.e., hematopoiesis). HSCs differentiate into a multipotent stem cell and this leads to lymphoid and myeloid progenitor cells. Lymphoid progenitors form natural killer T cells, T lymphocytes, and B lymphocytes. Myeloid progenitors form the RBCs, platelets, neutrophils, eosinophils, and basophils.
Apoptosis
One of the important functions of HSCs is regulation of the stem cell population and through apoptosis, programmed cell death; they maintain a tight control on the levels of blood cells. Growth factor signals were isolated that prevented the stem cells from undergoing apoptosis; one of which was the protein BCL-2, and the applications of this would be to maintain cultures of HSCs in the future.
Sources
Bone marrow
One of the earliest sources of HSCs identified was the bone marrow, especially the marrow of the pelvis, sternum, and femur. These formed the earliest of stem cell therapies, with the first syngeneic bone marrow transplant performed by hematologist E. Donnall Thomas as a treatment for acute lymphoblastic leukemia, for which he won the Nobel Prize.
Peripheral blood
Another source known to have a small amount of HSCs was peripheral blood, and over recent years it has replaced bone marrow transplants as a treatment for cancer, as cytokines such as GM-CSF are injected to increase the HSCs migration into peripheral blood and purified CD34+ or CD133+ stem cells are obtained.
Umbilical cord/placental blood.
Another rich source of HSCs identified in the late 1900s was placental and umbilical cord blood, and one of the first transplants was in a young boy with Fanconi’s anemia in France in 1988. The application of cord blood in adults is limited due to the inadequate number of HSCs that can be harvested from the source; however, it has become a mainstay in the treatment of younger patients.
Applications of Hematopoietic Stem Cells
Hematopoietic stem cell therapy takes three forms, classified according to the donor sources for transplant:
1 Allogeneic transplantation—the source is from another person (i.e., a related or unrelated donor according to the degree of HLA matching between the donor and the patient). A well-matched transplant decreases the risks of morbidity and mortality.
2 Autologous transplantation—the source is the patient and is usually used as a rescue therapy, to reconstitute the patient’s hematopoietic system after aggressive chemotherapy.
3 Syngeneic transplantation—the source is an identical twin, although the former two have taken precedence over this form of treatment in the recent years.
HSCs were first used for the treatment of leukemia and lymphomas, for inherited blood cell disorders and inborn errors of metabolism, autoimmune disorders, and in stem cell rescue following chemotherapy; some of the major indications for stem cell transplant in adults are listed in Table 1, and some of these pathologies will be discussed further on.
Table 1
Leukemia
Leukemia is a progressive malignant disorder marked by an increased number of immature and mature leukocytes, which in turn suppress the functions of the bone marrow and lead to pancytopenia. This pancytopenia results in anemia; as RBCs are depleted, there is a high infection rate due to the decreased leukocytes, and there are bleeding disorders due to decreased platelets.
There are four types of leukemia: acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML). Of these types, ALL is commonly found in children but may affect adults too.
One of the first applications for HSCs was the bone marrow transplant done to cure ALL, and over the course of the years Thomas discovered that CML, which was deemed fatal, could be cured by stem cell transplant. However, there were risks associated with this type of treatment. Now HSCs are usually acquired from the peripheral blood and are given to the patient after aggressive chemotherapy (which destroys the cancer cells) in order to reinstate the patient’s hematopoietic system, and this has yielded promising results.
In recent years, Imatinib Mesylate has been shown to target the cancer cells in CML by targeting the tyrosine kinase of the BCR-ABL gene, and it is proving to be a more suitable form of treatment over transplants due to the decreased risk of graft-versus-host disease.
Inherited Anemias
Allogeneic bone marrow transplants have also been used in the treatment of hereditary blood conditions, including beta thalassemia, aplastic anemia, Fanconi anemia, and sickle cell anemia; however, due to the risks associated with this, this is rarely used unless the condition is fatal.
Thalassemia is a disorder commonly found in Mediterranean people and is of two types: alpha and beta. In beta thalassemia, the beta globulin chain is absent in the hemoglobin and it leads to severe lifelong anemia, requiring frequent transfusions and thus causes a poorer quality of life.
Sickle cell anemia