BLOOD CELL PROGENITOR
dr.anny mariani sanusi, Prof. Dr. dr. H. Dasril Daud, Sp.A (K)
Dr. dr. Nadirah Rasyid Ridha, M.Kes.Sp.A (K)
Maximow (1924) put forward a postulate that red blood cells originate from a single stem cell. Then it was developed by Downey (1938) who made a hypothesis with the concept of a hierarchy of pluripotent cells. Then the concept of hematopoiesis derived from pluripotent stem cells was presented by Jacobson in (1949) and then Till and McCuloch (1961) concluded that a single stem cell is a colony that shows multilineage differentiation which means pluripotent into erythroid, myeloid and megakaryocytes. (1)
Hematopoiesis is a process of production, development and maturation of blood cellular elements. The development of hematopoiesis in the human embryo and fetus is divided into 3 anatomical levels: mesoblastic, hepatic, and myeloid. Mesoblastic hematopoiesis is found in the yolk sac starting from 2 weeks until the fetal period of 2 months is a period of erythropoiesis that produces erythroblasts and embryonic hemoglobin such as Gower Hb I and II, Portland Hb which does not reach adulthood. At 2-7 months of gestation, the hematopoiesis moves to the liver and the spleen then moves to the bone marrow. In adulthood, the process of hematopoiesis is present in the vertebrae, sternum, head, sacrum and pelvis, proximal to the femur (figure 1). (1,2)
Primitive hematopoiesis is limited to the formation of nucleated erythrocytes that express embryonic hemoglobin and macrophages. Definitive hematopoiesis is the process by which all types of blood cells are formed followed by their differentiation, including the enucleation of erythrocytes. (2,3)
All types of peripheral blood cells and some tissue cells in the body are derived from hematopoiesis stem cells (hamo = blood, poiesis = creation). The process of hematopoiesis in haemopoietic stem cells (HSCs) has the characteristics of blood cell descent and constant cell proliferation to maintain the number of circulating erythrocytes, leukocytes, and platelets throughout life. In childhood to adulthood, the bone marrow is the largest site for the process of hematopoiesis in humans, lasts long term and is capable of self-renewal and differentiation. This process is influenced by hematopoietic growth factors (growth factors) and cytokines. The haematopoiesis system is a hierarchical multipotent haemopoietic stem cell with offspring from stem cells (progenitor cells), then divides itself with the next generation of maturation processes and becomes mature blood cells. (figure 2)(4,5,6)
The hematopoietic system is divided into 3, namely (1):
1. Stem cells (early progenitors) that support hemopoiesis.
2. Colony forming unit (CFU) as a pioneer which further develops and differentiates in producing cells.
3. Growth factors and cytokines are regulators of blood cell production that will produce several types of cells with different locations in the body. In the next process, it is known that the regulation of hematopoiesis is very complex and many growth factors function overlap and there are many places for the production of these factors.
Stem cells are early progenitors that support hematopoiesis and cannot be recognized by staining only on the bone marrow. Then they develop into stem cells (progenitors) that can renew themselves and have the ability to differentiate according to lineage and then mature, function and end with cell death (apoptosis). The morphology of hemopoietic stem cells is nucleated cells that are phenotypically indistinguishable but immunological tests (immunophenotype) show CD34+, Thy-1+, Ac133+, c-Kit and CD33-, CD38-,Lin-, HLA-DR-. The best marker for stem cells and progenitor cells in humans is CD34. It is known that a number of cytokines and growth factors that have a role in the process of hematopoiesis, among others, act on the stromal: IL-1, TNF; in pluripotent stem cells: SCF, FLT3-L, VEGF; on multipotential progenitor cells: IL-3, GM-CSF, IL-6, G-CSF, thrombopoietin: on committed progenitor cells: G-CSF, M-CSF, IL-5 (eosinophil-CSF), erythropoietin, thrombopoietin. The roles of cytokinins in cell modification include: IL-2 on T and NK cells, IL-3 on multilineage stimulating factors, IL-4 on B, T and mast cells, IL-6 on stem and B cells, IL-7 on mast cells. pre-B, early T granulocytes, IL-11 in megakaryocytes, GM-CSF in granulocytes, macrophages, fibroblasts, endothelial cells, and EPO on red blood cell progenitors.
The general characteristics of growth factors from myeloid and lymphoid are glycoproteins that act at very low concentrations, act hierarchically, are produced in many cell types, are active on stem/progenitor cells, interact synergistically or adaptively with other growth factors, have a role in proliferation, differentiation, maturation, functional activation and preventing apoptosis of progenitor cells.
Clinical applications of stem cell research include:
1. Bone marrow and stem cell transplantation.
2. Stimulation of cell production in cytopenia patients by giving hematopoietic growth factors such as G-CSF, GM-CSF and erythropoietin.
3. Mobilization of stem cells using G-CSF (peripheral blood progenitor cells/PBPCs) into peripheral blood as a source of stem cells for transplantation.
4. Stem cell expansion: in the case of insufficient stem cells, the stem cell population is propagated to grow with a combination of cytokines.
5. Gene therapy: haematopoetic ability of stem cells as an option for the treatment of genetic disorders.
Stem and progenitor cell characterization in Bone Marrow (BM) relies on specific surface markers that allow subpopulations of cells to be isolated using Fluorescence Activated Cell Sorting (FACS) (Akashi et al., 2000, Kondo et al., 1997). An in vitro test (Colony Forming Unit or CFU assay) is used to study what types of cells are produced by isolated progenitor cells. Such assays have revealed lineage potential of progenitor cells in defined environments. (Cytokines and growth factors influenced the results of the analysis.) It is thought that the subset of BM cells isolated by FACS using antibodies directed against a specific set of surface markers is functionally homogeneous (Manz et al., 2002), and based on this, a cellular pyramidal shape, has been suggested to explain the development and expansion of the blood cell lineage (Fig. According to this model, oligopotent HSCs that reproduce all blood cell types differentiate into a variety of multipotent progenitors capable of giving rise to some, but not all, of these blood cells. Multipotent progenitors, in turn, produce unipotent cells that can only differentiate into a single blood cell lineage. (4,5)
Although several groups have questioned the specific details of the model outlined above (Adolfsson et al., 2005, Mansson et al., 2007) no one has until now attempted to re-evaluate (and re-imagine) the entire process. This is what Notta and his colleagues will do. They obtained samples of fetal liver, umbilical cord blood, and bone marrow aspirates from normal subjects and patients with aplastic anemia, and developed a novel cell sequencing method that appears to resolve myeloid, erythroid and megakaryocytic lineages generated from single CD34 progenitor cells. They then created assays that allowed them to evaluate the potential of sequenced single-cell lineages, and a profiling expression technique that could be applied to thousands of HSCs and progenitors isolated from cord blood.(4)
Stem cell is a stem cell (clonal) which has 2 characteristics, namely the ability to differentiate into several derivatives, divide and renew its own stem cell population (proliferation), under the influence of hemopoiesis growth factors. Stem cells (pluripotential) are the most primitive hemopoiesis stem cells, derived from mesenchymal (mesodermal) cells. These cells produce 2 different types of stem cells, namely multipotent myeloid stem cells and lymphoid stem cells. Stem cells have the ability to maintain their number by means of proliferation and are able to mature into other types of cells. Lymphoid stem cells produce lymphocyte progenitor cells of types T, B, non T and non B. Multipotent myeloid stem cells differentiate into various progenitor cells into erythrocytes, neutrophils and monocytes, eosinophils, basophils and platelets. Stem cells have the ability to self-renew so that although the bone marrow is the main site of new cell production, the overall cell count remains constant in a normal, balanced state.
In newborns, all bone marrow is Red Bone Marrow (RBM) which is active in the production of blood cells. As the individual grows, the average blood cell production decreases. RBM in the medullar cavity of long bones becomes inactive and is replaced by Yellow Bone Marrow (YBM) which are fat cells. Under certain conditions, such as when bleeding occurs, YBM can turn into RBM with RBM extension towards YBM, and YBM repopulation by pluripotent stem cells.
Stem cells in RBM reproduce themselves, proliferate, and differentiate into cells which will then develop into blood cells, macrophages, reticular cells, mast cells and adipocytes. Some stem cells also form osteoblasts, chondroblasts and muscle cells. Reticular cells produce reticular fibers, which form the stroma to support RBM cells. When blood cells are finished being produced in the RBM, they enter the blood circulation through the sinusoids (sinuses), capillaries that enlarge and surround the cells and fibers of the RBM. With the exception of lymphocytes, blood cells do not divide after leaving the RBM.
To form blood cells, the pluripotent stem cells in RBM produce 2 types of advanced stem cells, which have the ability to develop into several types of cells. These cells are called myeloid stem cells and lymphoid stem cells. Myeloid cells begin their development in the RBM, and will subsequently produce red blood cells, platelets, monocytes, neutrophils, eosinophils and basophils. Lymphoid cells begin to develop in the RBM and end their development in lymphatic tissues and eventually these cells will form lymphocytes.
Unlike stem cells, myeloid and lymphoid progenitor cells have a limited ability to proliferate. The less mature a progenitor cell type, the more capable it is to differentiate into 2 or 3 different differentiation pathways. The more mature the progenitor cell, the more limited its ability to differentiate until finally it is only able to differentiate in one pathway.
The earliest myeloid progenitors, capable of forming granulocytes, erythroblasts, monocytes and megakaryocytes, were named CFUGEMM (CFU-Colony Forming Unit). More mature and specialized progenitors named CFUGM (granulocytes and monocytes), CFUEO (eosinophil), CFUe (erythroid), and CFU meg (megakaryocyte), BFUe (burst forming unit, erythroid) are erythroid progenitors.
During hematopoiesis, some myeloid cells differentiate into progenitor cells. Other myeloid cells and lymphoid cells develop directly into precursor cells. Progenitor cells no longer have the ability to reproduce themselves, and instead form more specific blood elements.
Is a derivative of progenitor. Early precursors proliferate but are limited, late precursors only differentiate into mature cells. Precursor cells can respond to various stimuli and hormonal messages by increasing the production of one or another cell line when demand increases.
At a later stage, these cells are called precursor cells, also known as blasts. Through several stages of division, these cells develop into true blood cells. Precursor cells can be recognized and distinguished by their microscopic appearance.