Hematopoiesis

What is hematopoiesis?

Hematopoiesis, also known as hemopoiesis, is defined as the process of blood cell production.

Trilineage hematopoiesis refers to the process by which three different blood cell lineages are produced: red blood cells (produced by erythropoiesis), certain white blood cells (produced by leukopoiesis) and platelets (produced by thrombopoiesis).

Where does hematopoiesis occur?

Bone marrow is the final site of hematopoiesis. However, during early embryogenesis, hematopoiesis begins in the yolk sac. Over time, as the fetus develops, blood cell production moves to newly developing organs including the spleen, liver and bone marrow. For much of the duration of pregnancy, the liver is the primary site of hematopoiesis, but this transitions to the bone marrow prior to birth.

While the liver and spleen maintain some ability to help support hematopoiesis in the first few weeks to months of life, bone marrow is the primary site of blood cell production throughout childhood and in adults.

Specifically, it is the red bone marrow where hematopoiesis occurs. Medullary hematopoiesis directly refers to hematopoiesis that occurs in the red bone marrow. Yellow bone marrow is normally a storage site for fat, but can be converted to red bone marrow in order to support hematopoiesis in extreme circumstances such as severe blood loss.

What is extramedullary hematopoiesis?

Extramedullary hematopoiesis refers to blood cell production that occurs outside of bone marrow, most often in the spleen or liver. In older children and adults, extramedullary hematopoiesis is usually associated with a response to infection or symptoms of disease such as anemia.

What signaling pathways influence hematopoiesis?

The origin and potential of the stem cells involved in hematopoiesis, both hematopoietic stem cells (HSCs) and pluripotent stem cells (PSCs), has a significant influence on the pathways that drive hematopoiesis and its outcomes. In both cases, hematopoiesis is strictly regulated by cytokines, growth factors, transcription factors and other molecules. Key signaling networks include:

• FLT3 signaling - FLT3 is a cytokine receptor belonging to the class III receptor tyrosine kinase group. It is expressed by myeloid, lymphoid and dendritic cells and plays a crucial role in the growth and differentiation of hematopoietic lineages. Its signaling is activated with the binding of cytokine FL to FLT3 (1).
• Interleukin-3 (IL-3) signaling – IL-3, a monomeric glycoprotein, is a growth and differentiation factor of the hematopoietic bone marrow cell. It is produced by lymphoid cells, mast cells and eosinophils. Well recognized for regulating hematopoiesis, IL-3 stimulates the proliferation and maintenance of hematopoietic stem and progenitor cells (2).
• Lymphotoxin β Receptor (LTβR) signaling - LTβR is a tumor necrosis factor receptor expressed by epithelial cells, stromal cells, dendritic cells and macrophages. Signaling occurs when this receptor interacts with its ligands membrane heterotrimeric lymphotoxin LTα1β2 and homotrimeric LIGHT (3).

Developmental signaling pathways including Wnt, Notch and Hedgehog also play an important role in regulating hematopoiesis during early embryonic stages and throughout life.

Dysregulation of components of these pathways is associated with dysregulation of hematopoiesis leading to blood cancers like leukemia, lymphoma and multiple myeloma. Many of the components are relevant to research studies supporting development of better and more targeted treatments for blood cancers.

What are the consequences of ineffective hematopoiesis?

As discussed above, dysregulated hematopoiesis leads to blood cancers. However, ineffective hematopoiesis also has health consequences including development of cytopenias – low blood cell counts.

Anemia, a low red blood cell count, reduces the amount of hemoglobin available to carry oxygen to the body’s tissues resulting in hypoxia that may manifest as overall weakness, tiredness and shortness of breath. Neutropenia, a low white blood cell count, can lead to immunodeficiency and an inability to fight infection. Thrombocytopenia, a low platelet count, can impair blood clotting and lead to excessive bleeding – including internal bleeding.

In severe cases, ineffective hematopoiesis can lead to pancytopenia, low blood cell counts of all types, as the bone marrow becomes unable to produce sufficient blood cells.

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