- Hematopoiesis refers to the process that generates new, mature blood cells. All such cells ultimately derive from a single progenitor cell termed the Hematopoietic Stem Cell (HSC) which undergoes a process of highly regulated division and differentiation that produces the gamut of mature blood cells. Although during fetal life hematopoiesis begins in the yolk sac followed by a phase in the liver and spleen, by birth and throughout adult life hematopoiesis takes place in the bone marrow.
|The Hematopoietic Stem Cell|
- A large body of evidence supports the notion that all mature blood cells derive from a single cell type known as the "Hematopoietic Stem Cell" (HSC). As this cell divides, it's descendants begin to differentiate down particular pathways toward mature blood cells, akin to traveling from a tree trunk, down progressively thinner branches, toward a particular leaf. As these cells differentiate toward a particular cell type, they progressively lose their capacity to develop into the other cell types found in other branches of the differentiation tree.
- The overall architecture of this differentiation tree largely matches the basic categories of blood cells with pathways dedicated to making erythrocytes (erythropoiesis), lymphocytes (lymphopoiesis), granulocytes (granulopoiesis), monocytes (monopoiesis), and platelets (thrombopoiesis). Below we discuss these basic pathways and the intermediate cell types that define that differentiation pathway. An intimate understanding of these intermediate cell types is not necessary, but a broad understanding of the overall architecture of the differentiation tree may be helpful in appreciating the similarities and differences between mature blood cells.
- A final note: Hematopoiesis is a life-time activity and thus exhausting the supply of HSCs would be disastrous. Consequently, it is important to note that when a HSC divides, one daughter cell remains an HSC, while the other begins the process of differentiation, thus guaranteeing a lifetime supply of HSCs.
- The first cell stages committed to any pathway are typically termed "blasts". Blasts committed to the major differentiation pathways discussed below do display some unique morphological characteristics; however, in general all blasts are fairly similar and appear as large cells with large nuclei. Blasts are also characterized by extremely rapid cell division rates. As differentiation progresses, the rate of cell division declines and the cells acquire the morphological characteristics unique to their ultimate mature cell type. The progressive development of these unique morphological characteristics is used to define stages of differentiation.
- In certain pathological scenarios, such as acute leukemias, genetic lesions appear to block the differentiation of these blast cells, thus generating a neoplastic clone of undifferentiated cells with rapid mitotic rates.
- Erythropoiesis refers to the process which generates fully mature erythrocytes and requires the synthesis of vast amounts of hemoglobin along with the ultimate loss of the cell's nucleus and intracellular organelles. The first recognizable cell type that is fully committed to differentiating into an erythrocyte is termed the "Proerythroblast", a large nucleus-containing cell with no hemoglobin and prominent organelles.
- As this cell differentiates, its size becomes progressively smaller, organelles are lost, and its color changes from blue (basophilic) to pink (eosinophilic), reflecting decreasing content of hemoglobin-coding nucleotides (blue), and increasing content of actual proteinaceous hemoglobin (pink). As differentiation proceeds, the nucleus becomes increasingly small, compact, and is ultimately extruded from the cell.
- The cells which exit the bone marrow and into the circulation are not fully mature and still contain a small amount of nucleotide content that renders them slightly basophilic. These "reticulocytes" can be easily observed in the peripheral blood, and elevated levels (termed "Reticulocytosis") is an important indication that erythropoiesis is increased within the marrow.
- The entire process of erythropoiesis is regulated by erythropoietin, a soluble protein synthesized by the kidneys in response to low arterial oxygen tension within the blood. Thus when the blood's oxygen tension is low, increased eyrthropoietin levels stimulate enhanced erythropoiesis which boosts the levels of erythrocytes in the blood and thus enhance the blood's oxygen carrying capacity.
- Granulopoiesis refers to the process by which mature granulocytes differentiate within the bone marrow. The earliest stage cell which appears to be committed to the granulocyte lineage is the large rapidly dividing "Myeloblast" which upon developing cytoplasmic granules is termed the "Promyelocyte". The promyelocyte can then differentiate toward one of the three granulocyte lineages: neutrophil, eosinophil, or basophil. This differentiation process is characterized by the development of cytopasmic granules specific to the particular lineage as well as progressive segmentation of the nucleus.
- Monopoiesis refers to the process by which mature monocytes are generated within the bone marrow. These cells likely derive from a precursor in common with granulocytes, thus monopoiesis and granulopoiesis may branch from a single monocyte-granulocyte precursor. The first cell committed to the monocytic pathway is termed the "monoblast" which reduces in size and develops as indented nucleus as differentiation progresses.
- Lymphopoiesis refers to the process by which mature lymphocytes differentiate within the bone marrow. These cells derive from a common precursor known as the "lymphoblast" which subsequently differentiates into specific lymphocytic subtypes, including B-cells, T-cells, and Natural Killer Cells. Unlike other blood cells, B-cells and T-cells are not fully mature upon exiting the bone marrow and undergo an elaborate process of differentiation in the spleen and thymus, respectively, as discussed in more detail in B-cell Development and T-cell Development.
- Thrombopoiesis refers to the process by which mature platelets are generated within the bone marrow. Platelets are produced by the megakaryocyte, an extremely large cell within the bone marrow that is saturated with granule-like organelles. Individual platelets are generated by fragmentation of the megakaryocyte plasma membrane, generating small membrane-bound platelets enveloping numerous granules. These granules are released upon activation of the platelet in a process known as platelet plugging.
- Megakaryocytes themselves are long-lived cells that continuously produce platelets and are thus in a constant state of membrane fragmentation and loss. These cells differentiate relatively early from the primordial Hematopoietic Stem Cell and go through a number of stages before fully maturing.