Hematopoiesis

What is hematopoiesis?

Hematopoiesis, also known as hemopoiesis, is the process of production of all types of blood cells.

Trilineage hematopoiesis refers to the process by which three major blood cell lineages are produced: red blood cells via erythropoiesis, certain white blood cells via leukopoiesis and platelets via by thrombopoiesis. The process follows a hierarchical differentiation model, beginning with multipotent hematopoietic stem cells (HSCs) that give rise to common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs). These progenitors further specialize into committed precursors and mature blood cells under the influence of both intrinsic transcriptional programs and external niche signals.

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. While normal during fetal development, it is rare in healthy adults and usually signifies a pathologic response to conditions such as chronic anemia, myelofibrosis or severe infection. These sites can partially recapitulate the bone marrow microenvironment, supporting the maturation of certain blood cell types.

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 tightly regulated by a network of cytokines, growth factors and transcription factors. Among the key regulators are stem cell factor (SCF) acting via c-Kit to promote stem cell maintenance, erythropoietin (EPO) to stimulate red cell production, thrombopoietin (TPO) to regulate platelet formation, granulocyte colony-stimulating factor (G-CSF) to enhance neutrophil output and granulocyte-macrophage colony-stimulating factor (GM-CSF) to support myeloid differentiation.

 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: the membrane heterotrimeric lymphotoxin LTα1β2 and homotrimeric LIGHT (3).

Developmental signaling pathways including Wnt, Notch and Hedgehog, guide early lineage decisions, while transcription factors including PU.1, GATA-1 and C/EBPα direct lineage commitment.

The hematopoietic stem cell niche within bone marrow, comprising stromal cells, osteoblasts, endothelial cells and extracellular matrix, provides physical and molecular cues that maintain the balance between quiescence, self-renewal and differentiation. Disruption of this microenvironment can impair hematopoiesis or promote malignant transformation

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). Inability of bone marrow to produce sufficient mature blood cells can result in anemia, neutropenia or thrombocytopenia:

• Anemia, a low red blood cell count, reduces the amount of hemoglobin available to carry oxygen to the body’s tissues. Less hemoglobin in circulation results in hypoxia (low levels of oxygen within tissues), in particular in the cardiovascular system, 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. Neutrophils act as the first line of defense against invading pathogens, particularly bacteria and fungi. When neutrophil levels are low, this immediate immune response is impaired, leading to increased susceptibility to infections. The severity of immunodeficiency correlates with the severity and duration of the period of neutropenia.
• 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.

References

1. Tsapogas P, Mooney CJ, Brown G, Rolink A. The cytokine Flt3-ligand in normal and malignant hematopoiesis. Int J Mol Sci. 2017;18(6):1115.
2. Tajer P, Canté-Barrett K, Naber BAE, et al. IL3 has a detrimental effect on hematopoietic stem cell self-renewal in transplantation settings. Int J Mol Sci. 2022;23(21):12736.
3. Shou Y, Koroleva E, Spencer CM, et al. Redefining the role of lymphotoxin beta receptor in the maintenance of lymphoid organs and immune cell homeostasis in adulthood. Front Immunol. 2021;12:712632.